| YUJI ISHII | Last modified date：2024.04.19 |
Associate Professor /
Department of Medico-Pharmaceutical Sciences /
Department of Pharmaceutical Health Care and Sciences /
Faculty of Pharmaceutical Sciences
Papers
| 1. | Jorge Carlos Pineda Garcia, Ren-Shi Li, Ruri Kikura-Hanajiri, Yoshitaka Tanaka, Yuji Ishii, Timeframe Analysis of Novel Synthetic Cannabinoids Effects: A Study on Behavioral Response and Endogenous Cannabinoids Disruption, International Journal of Molecular Sciences, 10.3390/ijms25063083, 25, 6, 3083-3083, 2024.03. |
| 2. | Takayuki Koga, Kie Inoue, Fuka Hirayama, Makoto Hiromura, Kiyonaga Fujii, Yuji Ishii, Masayo Hirao-Suzuki, Shuso Takeda, Akihisa Toda, Fumio Soeda, Dimethylglycine, a Methionine Metabolite, Participates in the Suppressive Effect of Methionine on 1-Fluoro-2,4-dinitrobenzene-Induced Dermatitis, Biological & Pharmaceutical Bulletin, 10.1248/bpb.b23-00098, 46, 7, 946-954, 2023.07. |
| 3. | Ming Yuan, Hiroe Sano, Takaaki Nishino, Hongbin Chen, Ren-Shi Li, Yuki Matsuo, Kyoko Nishida, Takayuki Koga, Tomoki Takeda, Yoshitaka Tanaka, Yuji Ishii
, α-Lipoic acid eliminates dioxin-induced offspring sexual immaturity by improving abnormalities in folic acid metabolism, Biochemical Pharmacology, 10.1016/j.bcp.2023.115490, 210, 115490-115490, 2023.04, . |
| 4. | Hiroyuki Mohri, Kazuko Mohri, Akinaga Gohda, Yuji Ishii, Rapid derivatization of phosphorus-containing amino acid herbicides in plasma and urine using microwave heating, Journal of Toxicological Sciences, 10.2131/jts.48.15, 48, 1, 15-24, 2023.01. |
| 5. | Yuu Miyauchi, Akane Kimura, Madoka Sawai, Keiko Fujimoto, Yuko Hirota, Yoshitaka Tanaka, Shinji Takechi, Peter I Mackenzie, Yuji Ishii, Use of a Baculovirus-Mammalian Cell Expression-System for Expression of Drug-Metabolizing Enzymes: Optimization of Infection With a Focus on Cytochrome P450 3A4, Frontiers in Pharmacology, 10.3389/fphar.2022.832931, 13, 832931-832931, 2022.02. |
| 6. | Renshi Li, Xuewei Peng, Yanliang Wu, Weichao Lv, Haifeng Xie, Yuji Ishii, Chaofeng Zhang, Exposure to PM2.5 during pregnancy causes lung inflammation in the offspring: mechanism of action of mogrosides., Ecotoxicology and Environmental Safety, https://doi.org/10.1016/j.ecoenv.2021.112955, 228, 112955-112955, (2021) , 2021.11. |
| 7. | Hong-bin Chen, Jorge Carlos Pineda Garcia, Shinako Arizono, Tomoki Takeda, Ren-shi Li, Yukiko Hattori, Hiroe Sano, Yuu Miyauchi, Yuko Hirota, Yoshitaka Tanaka, Yuji Ishii, DAPL1 is a novel regulator of testosterone production in Leydig cells of mouse testis, Scientific Reports, 10.1038/s41598-021-97961-6., 11, 1, 18532, 2021.09.  |
| 8. | Shoji Nakamura, Ryohei Yamashita, Yuu Miyauchi, Yoshitaka Tanaka, Yuji Ishii, Adenine-related compounds modulate UDP-glucuronosyltransferase (UGT) activity in mouse liver microsomes, Xenobiotica, 10.1080/00498254.2021.2001075, 51, 11, 1247-1254, 2021.10. |
| 9. | Yingxia Song, Atsushi Kurose, Renshi Li, Tomoki Takeda, Yuko Onomura, Takayuki Koga, Junpei Mutoh, Takumi Ishida, Yoshitaka Tanaka, Yuji Ishii, Ablation of Selenbp1 Alters Lipid Metabolism via the Pparα Pathway in Mouse Kidney., International Journal of Molecular Sciences, 10.3390/ijms22105334., 22, 10, 5334, 2021.05, Selenium-binding protein 1 (Selenbp1) is a 2,3,7,8-tetrechlorodibenzo-p-dioxin inducible protein whose function is yet to be comprehensively elucidated. As the highly homologous isoform, Selenbp2, is expressed at low levels in the kidney, it is worthwhile comparing wild-type C57BL mice and Selenbp1-deficient mice under dioxin-free conditions. Accordingly, we conducted a mouse metabolomics analysis under non-dioxin-treated conditions. DNA microarray analysis was performed based on observed changes in lipid metabolism-related factors. The results showed fluctuations in the expression of numerous genes. Real-time RT-PCR confirmed the decreased expression levels of the cytochrome P450 4a (Cyp4a) subfamily, known to be involved in fatty acid ω- and ω-1 hydroxylation. Furthermore, peroxisome proliferator-activated receptor-α (Pparα) and retinoid-X-receptor-α (Rxrα), which form a heterodimer with Pparα to promote gene expression, were simultaneously reduced. This indicated that reduced Cyp4a expression was mediated via decreased Pparα and Rxrα. In line with this finding, increased levels of leukotrienes and prostaglandins were detected. Conversely, decreased hydrogen peroxide levels and reduced superoxide dismutase (SOD) activity supported the suppression of the renal expression of Sod1 and Sod2 in Selenbp1-deficient mice. Therefore, we infer that ablation of Selenbp1 elicits oxidative stress caused by increased levels of superoxide anions, which alters lipid metabolism via the Pparα pathway.. |
| 10. | Yuko Hirota, Masaharu Hayashi, Yuu Miyauchi, Yuji Ishii, Yoshitaka Tanaka, Keiko Fujimoto, LAPTM4α is targeted from the Golgi to late endosomes/lysosomes in a manner dependent on the E3 ubiquitin ligase Nedd4-1 and ESCRT proteins., Biochemical and biophysical research communications, 10.1016/j.bbrc.2021.03.151, 556, 9-15, 2021.04. |
| 11. | Yukiko Hattori, Tomoki Takeda, Misaki Fujii, Junki Taura, Hideyuki Yamada, Yuji Ishii, Attenuation of growth hormone production at the fetal stage is critical for dioxin-induced developmental disorder in rat offspring., Biochemical pharmacology, 10.1016/j.bcp.2021.114495, 186, 114495-114495, 2021.03, Although dioxins and related chemicals have been suspected to disrupt child development, their toxic mechanism remains poorly understood. Our previous studies in rat fetuses revealed that maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly-toxic dioxin, suppresses fetal synthesis of pituitary growth hormone (GH) that is essential for development. This study examined the hypothesis that attenuating GH expression in fetuses triggers developmental disorders. Treating pregnant rats with 1 μg/kg TCDD reduced the circulating level of GH and its downstream factor, insulin-like growth factor-1 (IGF-1), in the offspring only during the fetal and early neonatal stages. Although maternal TCDD exposure resulted in low body weight and length at babyhood and defects in the learning and memory ability at adulthood, GH supplementation in TCDD-exposed fetuses restored or tended to restore the defects including IGF-1 downregulation. Moreover, maternal TCDD exposure decreased the number of GH-positive cells during the fetal/neonatal stage. A microarray analysis showed that TCDD reduced the expression of death-associated protein-like 1 (DAPL1), a cell cycle-dependent proliferation regulator, in the fetal pituitary gland. In addition, TCDD treatment attenuated proliferating cells and cyclin mRNA expression in the fetal pituitary gland. Aryl hydrocarbon receptor (AHR)-knockout fetuses were insensitive to TCDD treatment, indicating that the TCDD-induced reduction in DAPL1 and GH mRNAs expression was due to AHR activation. Finally, DAPL1 knockdown suppressed GH and cyclin D2 expression in fetal pituitary cells. These results provide a novel evidence that dioxin suppresses GH-producing cell proliferation and GH synthesis due to partly targeting DAPL1, thereby impairing offspring development.. |
| 12. | Chie Yokouchi, Yukari Nishimura, Hirohiko Goto, Makoto Sato, Yuya Hidoh, Kenji Takeuchi, YUJI ISHII, Reduction of fatty liver in rats by nicotinamide via the regeneration of the methionine cycle and the inhibition of aldehyde oxidase, J. Toxicol. Sci., 46, 1, 31-42, 2021.01. |
| 13. | Takayuki Koga, Fuka Hirayama, Tomomitsu Satoh, Yuji Ishii, Nobuhiro Kashige, Makoto Hiromura, Fumio Soeda, Akihisa Toda, Methionine is a Key Regulator in the Onset of Atopic Dermatitis in NC/Nga Mice, BPB Reports, 4, 47-54, 2021.01. |
| 14. | Yuu Miyauchi, Ken Kurohara, Akane Kimura, Madoka Esaki, Keiko Fujimoto, Yuko Hirota, Shinji Takechi, Peter I Mackenzie, Yuji Ishii, Yoshitaka Tanaka, The carboxyl-terminal di-lysine motif is essential for catalytic activity of UDP-glucuronosyltransferase 1A9., Drug metabolism and pharmacokinetics, 10.1016/j.dmpk.2020.07.006, 35, 5, 466-474, 2020.10, UDP-Glucuronosyltransferase (UGT) is a type I membrane protein localized to the endoplasmic reticulum (ER). UGT has a di-lysine motif (KKXX/KXKXX) in its cytoplasmic domain, which is defined as an ER retention signal. However, our previous study has revealed that UGT2B7, one of the major UGT isoform in human, localizes to the ER in a manner that is independent of this motif. In this study, we focused on another UGT isoform, UGT1A9, and investigated the role of the di-lysine motif in its ER localization, glucuronidation activity, and homo-oligomer formation. Immunofluorescence microscopy indicated that the cytoplasmic domain of UGT1A9 functioned as an ER retention signal in a chimeric protein with CD4, but UGT1A9 itself could localize to the ER in a di-lysine motif-independent manner. In addition, UGT1A9 formed homo-oligomers in the absence of the motif. However, deletion of the di-lysine motif or substitution of lysines in the motif for alanines, severely impaired glucuronidation activity of UGT1A9. This is the first study that re-defines the cytoplasmic di-lysine motif of UGT as an essential peptide for retaining glucuronidation capacity.. |
| 15. | Keiko Fujimoto, Sanae Nakashima, Shotaro Uchida, Riham N S Amen, Yuji Ishii, Yuko Hirota, Yoshitaka Tanaka, HM1.24/BST-2 is constitutively poly-ubiquitinated at the N-terminal amino acid in the cytoplasmic domain., Biochemistry and biophysics reports, 10.1016/j.bbrep.2020.100784, 23, 100784-100784, 2020.09, HM1.24 (also known as BST-2, CD317, and Tetherin) is a type II single-pass transmembrane glycoprotein, which traverses membranes using an N-terminal transmembrane helix and is anchored in membrane lipid rafts via a C-terminal glycosylphosphatidylinositol (GPI). HM1.24 plays a role in diverse cellular functions, including cell signaling, immune modulation, and malignancy. In addition, it also functions as an interferon-induced cellular antiviral restriction factor that inhibits the replication and release of diverse enveloped viruses, and which is counteracted by Vpu, an HIV-1 accessory protein. Vpu induces down-regulation and ubiquitin conjugation to the cytoplasmic domain of HM1.24. However, evidence for ubiquitination site(s) of HM1.24 remains controversial. We demonstrated that HM1.24 is constitutively poly-ubiquitinated at the N-terminal cytoplasmic domain, and that the mutation of all potential ubiquitination sites, including serine, threonine, cysteine, and lysine in the cytoplasmic domain of HM1.24, does not affect the ubiquitination of HM1.24. We further demonstrated that although a GPI anchor is necessary and sufficient for HM1.24 antiviral activities and virion-trapping, the deleted mutant of GPI does not influence the ubiquitination of HM1.24. These results suggest that the lipid raft localization of HM1.24 is not a prerequisite for the ubiquitination. Collectively, our findings demonstrate that the ubiquitination of HM1.24 occurs at the N-terminal amino acid in the cytoplasmic domain and indicate that the constitutive ubiquitination machinery of HM1.24 may differ from the Vpu-induced machinery.. |
| 16. | Masayo Hirao-Suzuki, Takayuki Koga, Genki Sakai, Takanobu Kobayashi, Yuji Ishii, Hiroshi Miyazawa, Masafumi Takiguchi, Narumi Sugihara, Akihisa Toda, Masahiro Ohara, Shuso Takeda, Fatty acid 2-hydroxylase (FA2H) as a stimulatory molecule responsible for breast cancer cell migration, Biochem. Biophys. Res. Commun., in press., 2020.07. |
| 17. | Tomoki Takeda, Misaki Fujii, Waka Izumoto, Yukiko Hattori, Takeshi Matsushita, Hideyuki Yamada, Yuji Ishii, Gestational dioxin exposure suppresses prolactin-stimulated nursing in lactating dam rats to impair development of postnatal offspring., Biochemical pharmacology, 10.1016/j.bcp.2020.114106, 178, 114106-114106, 2020.06, A number of epidemiological studies have implicated environmental chemicals including dioxins in the induction of negative effects on child development. To clarify the underlying mechanisms, almost all toxicologists have concentrated on effects on the offspring themselves. We examined an alternative hypothesis that gestational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly-toxic dioxin, targets factors related to maternal childcare to disturb offspring development. Oral administration of TCDD (1 µg/kg) to pregnant rats on gestational day 15 suppressed maternal licking behavior, a nursing behavior, and mammary gland maturation during the lactational stage, as well as the body weight and short-term memory of postnatal offspring. In support of these findings, maternal production of prolactin, a pituitary hormone essential for nursing including milk production, was decreased during the same period. Intracerebroventricular infusion of prolactin to dioxin-exposed dams restored or tended to restore many of the above defects observed both in mothers and offspring. The TCDD-dependent defects in maternal nursing behaviors can be due to a direct action on aryl hydrocarbon receptor (AHR) of lactating dams, because they did not emerge in AHR-knockout dams or control dams with TCDD-exposed offspring. Further examinations revealed that TCDD induces transforming growth factor β1 expression, which suppresses prolactin-producing cell proliferation, in a nursing period-specific manner. In agreement with this, the number of prolactin-positive cells in nursing dams was decreased by TCDD. These results provide novel evidence that gestational dioxin exposure attenuates prolactin-stimulated nursing in lactating dams to impair offspring development, and that immaturity of prolactin-producing cells can contribute to them.. |
| 18. | Yuu Miyauchi, Ayumi Kurita, Ryohei Yamashita, Tomoyuki Takamatsu, Shin'ichi Ikushiro, Peter I. Mackenzie, Yoshitaka Tanaka, Yuji Ishii, Hetero-oligomer formation of mouse UDP-glucuronosyltransferase (UGT) 2b1 and 1a1 results in the gain of glucuronidation activity towards morphine, an activity which is absent in homo-oligomers of either UGT, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2020.02.075, 525, 2, 348-353, 2020.04, UDP-Glucuronosyltransferase (UGT, Ugt) is a major drug metabolizing enzyme family involved in the glucuronidation and subsequent elimination of drugs and small lipophilic molecules. UGT forms homo- and hetero-oligomers that enhance or suppress UGT activity. In our previous study, we characterized mouse Ugt1a1 and all the Ugt isoform belonging to the Ugt2b subfamily and revealed that mouse Ugt2b1 and Ugt1a1 cannot metabolize morphine. Mouse Ugt2b1 had been believed to function similarly to rat UGT2B1, which plays a major role in morphine glucuronidation in rat liver. Thus, in this study, we hypothesized that hetero-oligomerization with another Ugt isoform may affect Ugt2b1 catalytic ability. We co-expressed Ugt1a1 and Ugt2b1 in a baculovirus-insect cell system, and confirmed hetero-oligomer formation by co-immunoprecipitation. As reported previously, microsomes singly expressing Ugt1a1 or Ugt2b1 were inactive towards the glucuronidation of morphine. Interestingly, in contrast, morphine-3-glucuronide, a major metabolite of morphine was formed, when Ugt2b1 and Ugt1a1 were co-expressed. This effect of hetero-oligomerization of Ugt1a1 and Ugt2b1 was also observed for 17β-estradiol glucuronidation. This is the first report demonstrating that UGT acquires a novel catalytic ability by forming oligomers. Protein-protein interaction of Ugts may contribute to robust detoxification of xenobiotics by altering the substrate diversity of the enzymes.. |
| 19. | Keiko Fujimoto, Shotaro Uchida, Riham N.S. Amen, Yuji Ishii, Yoshitaka Tanaka, Yuko Hirota, Lysosomal integral membrane protein LGP85 (LIMP-2) is ubiquitinated at the N-terminal cytoplasmic domain, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2020.01.095, 524, 2, 424-430, 2020.04, LGP85/LIMP-2 is a type III transmembrane glycoprotein of lysosomes, which traverses the membrane twice with an N-terminal uncleaved signal sequence and C-terminal hydrophobic domain. In addition to functioning as a receptor for a lysosomal enzyme β-glucocerebrosidase and for several enteroviruses, LGP85 plays a key role in the biogenesis and maintenance of endosomal/lysosomal compartments (ELCs). Our previous studies have demonstrated that overexpression of rat LGP85 into COS cells results in the enlarged ELCs, from where membrane trafficking is impaired. We show here that rat LGP85 is polyubiquitinated at the N-terminal short cytoplasmic domain that comprises of only three amino acid residues, alanine, arginine, and cysteine. Replacement of either arginine or cysteine with alanine within the N-terminal cytoplasmic domain did not influence the ubiquitination of LGP85, thereby indicating that ubiquitin (Ub) is conjugated to the α-NH2 group of the N-terminal alanine residue. Furthermore, we were able to define a domain necessary for ubiquitination in a region ranging from the amino acids 156 to 255 within the lumenal domain of LGP85. This is the first report showing that the integral lysosomal membrane protein LGP85 is ubiquitinated.. |
| 20. | Masahiro Yahata, Yuji Ishii, Tetsuya Nakagawa, Takao Watanabe, Izuru Miyawaki, Applicability of the Øie-Tozer model to predict three types of distribution volume (Vd) in humans Vd in central compartment, Vd at steady state, and Vd at beta phase, Biopharmaceutics and Drug Disposition, 10.1002/bdd.2224, 2020.01, This study aimed to investigate the applicability of the Øie-Tozer model to predict human distribution volume (Vd) in the central compartment (V1), Vd at steady state (Vdss), and Vd at beta phase (Vdβ) based on animal Vd. Twenty compounds that have a human V1/Vdss of 0.053–0.66 were selected from the literature. After intravenous administration of the compounds at 0.1 mg/kg to rats, dogs, and monkeys, plasma concentrations were determined, and pharmacokinetic parameters were obtained by one/two-compartmental analyses. The human V1, Vdss, and Vdβ were predicted from animal Vd using the Øie-Tozer model, and the predictability was compared with that using proportionality and simple allometry. The Øie-Tozer model was the most reliable method for the overall prediction of Vd and applicable for accurately predicting human V1, Vdss, and Vdβ (89%, 85%, and 68% of the compounds within a 3-fold error, respectively) when data of monkey for V1 and data of three animal species for Vdss and Vdβ were used. Additionally, the predicted human Vd with the two-compartment model was applicable for predicting pharmacokinetic profiles/parameters in humans after intravenous administration of 18 compounds [except for valproic acid (monophasic elimination profile) and chlorpromazine (deviation: Vdss 1)]. The prediction was more accurate than that using the predicted Vdss with the one-compartment model (e.g., underestimation of maximum plasma concentrations: 2 vs 8 compounds within a 3-fold error, respectively). In summary, the Øie-Tozer model was applicable for predicting human V1, Vdss, and Vdβ, and their predicted Vd with the two-compartment model can lead to accurate pharmacokinetic prediction of compounds that show biphasic elimination.. |
| 21. | Ren-shi Li, Gong-hao Xu, Juan Cao, Bei Liu, Hai-feng Xie, Yuji Ishii, Chao-feng Zhang, Alpha-Mangostin Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Mice Partly Through Activating Adenosine 5'-Monophosphate-Activated Kinase., Front. Pharmacol., 10.3389/fphar.2019.01305, 10, 1305, 2019.11. |
| 22. | Yuu Miyauchi, the late Hideyuki Yamada, YUJI ISHII, Advantage of a Co-expression System for Estimating Physiological Effects of Functional Interaction Between Cytochrome P450 3A4 and Uridine 5’-Diphospho-Glucuronosyltransferase 2B7, BPB Reports, 20, 5, 61-66, 2019.10. |
| 23. | Ren Shi Li, Ryo Fukumori, Tomoki Takeda, Yingxia Song, Satoshi Morimoto, Ruri Kikura-Hanajiri, Taku Yamaguchi, Kazuhito Watanabe, Kousuke Aritake, Yoshitaka Tanaka, Hideyuki Yamada, Tsuneyuki Yamamoto, Yuji Ishii, Elevation of endocannabinoids in the brain by synthetic cannabinoid JWH-018 mechanism and effect on learning and memory, Scientific reports, 10.1038/s41598-019-45969-4, 9, 1, 2019.07, The impairment of learning and memory is a well-documented effect of both natural and synthetic cannabinoids. In the present study, we aimed to investigate the effect of acute administration of JWH-018, a synthetic cannabinoid, on the hippocampal metabolome to assess biochemical changes in vivo. JWH-018 elevated levels of the endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The increase of endocannabinoid levels in response to JWH-018 could be inhibited by co-administration of AM251, a CB1 receptor antagonist. Biochemical analyses revealed that this was the result of suppression of two hydrolases involved in endocannabinoid degradation (fatty acid amide hydrolase [FAAH] and monoacylglycerol lipase [MAGL]). Additionally, we showed that JWH-018 causes a reduction in the levels of brain-derived neurotrophic factor (BDNF), which is known to modulate synaptic plasticity and adaptive processes underlying learning and memory. The decrease of BDNF following JWH-018 treatment was also rescued by co-administration of AM251. As both endocannabinoids and BDNF have been shown to modulate learning and memory in the hippocampus, the alteration of their levels in response to JWH-018 may explain the contribution of synthetic cannabinoids to impairment of memory.. |
| 24. | Yuu Miyauchi, Sora Kimura, Akane Kimura, Ken Kurohara, Yuko Hirota, Keiko Fujimoto, Peter I. Mackenzie, Yoshitaka Tanaka, Yuji Ishii, Investigation of the endoplasmic reticulum localization of UDP-glucuronosyltransferase 2B7 with systematic deletion mutants, Molecular Pharmacology, 10.1124/mol.118.113902, 95, 5, 551-562, 2019.05, UDP-Glucuronosyltransferase (UGT) plays an important role in the metabolism of endogenous and exogenous compounds. UGT is a type I membrane protein, and has a dilysine motif (KKXX/KXKXX) in its C-terminal cytoplasmic domain. Although a dilysine motif is defined as an endoplasmic reticulum (ER) retrieval signal, it remains a matter of debate whether this motif functions in the ER localization of UGT. To address this issue, we generated systematic deletion mutants of UGT2B7, a major human isoform, and compared their subcellular localizations with that of an ER marker protein calnexin (CNX), using subcellular fractionation and immunofluorescent microscopy. We found that although the dilysine motif functioned as the ER retention signal in a chimera that replaced the cytoplasmic domain of CD4 with that of UGT2B7, UGT2B7 truncated mutants lacking this motif extensively colocalized with CNX, indicating dilysine motif–independent ER retention of UGT2B7. Moreover, deletion of the C-terminal transmembrane and cytoplasmic domains did not affect ER localization of UGT2B7, suggesting that the signal necessary for ER retention of UGT2B7 is present in its luminal domain. Serial deletions of the luminal domain, however, did not affect the ER retention of the mutants. Further, a cytoplasmic and transmembrane domain–deleted mutant of UGT2B7 was localized to the ER without being secreted. These results suggest that UGT2B7 could localize to the ER without any retention signal, and lead to the conclusion that the static localization of UGT results from lack of a signal for export from the ER.. |
| 25. | Masahiro Yahata, Yuji Ishii, Tetsuya Nakagawa, Takao Watanabe, Kiyoko Bando, Species differences in metabolism of a new antiepileptic drug candidate, DSP-0565 [2-(2′-fluoro[1,1′-biphenyl]-2-yl)acetamide], Biopharmaceutics and Drug Disposition, 10.1002/bdd.2180, 40, 5-6, 165-175, 2019.05, The metabolism and pharmacokinetics of DSP-0565 [2-(2′-fluoro[1,1′-biphenyl]-2-yl)acetamide], an antiepileptic drug candidate, was investigated in rats, dogs, and humans. In human hepatocytes, [14C]DSP-0565 was primarily metabolized via amide bond hydrolysis to (2′-fluoro[1,1′-biphenyl]-2-yl)acetic acid (M8), while in rat and dog hepatocytes, it was primarily metabolized via both hydrolysis to M8 and hydroxylation at the benzene ring or the benzyl site to oxidized metabolites. After single oral administration of [14C]DSP-0565 to rats and dogs, the major radioactivity fraction was recovered in the urine (71–72% of dose) with a much smaller fraction recovered in feces (23–25% of dose). As primary metabolites in their excreta, M8, oxidized metabolites, and glucuronide of DSP-0565 were detected. The contribution of metabolic pathways was estimated from metabolite profiles in their excreta: the major metabolic pathway was oxidation (57–62%) and the next highest was the hydrolysis pathway (23–33%). These results suggest that there are marked species differences in the metabolic pathways of DSP-0565 between humans and animals. Finally, DSP-0565 human oral clearance (CL/F) was predicted using in vitro–in vivo extrapolation (IVIVE) with/without animal scaling factors (SF, in vivo intrinsic clearance/in vitro intrinsic clearance). The SF improved the underestimation of IVIVE (fold error = 0.22), but the prediction was overestimated (fold error = 2.4–3.3). In contrast, the use of SF for hydrolysis pathway was the most accurate for the prediction (fold error = 1.0–1.4). Our findings suggest that understanding of species differences in metabolic pathways between humans and animals is important for predicting human metabolic clearance when using animal SF.. |
| 26. | Jorge Carlos Pineda Garcia JC, Ren-shi Li, Ruri Kikura-Hanajiri, Yoshitaka Tanaka, Yuji Ishii, Timeframe Analysis of Novel Synthetic Cannabinoids Effects: A Study on Behavioral Response and Endogenous Cannabinoids Disruption, International Journal of Molecular Sciences, doi.org/10.3390/ijms25063083, 25, 6, 3083, 2024.03. |
| 27. | Kenji Takeuchi, Chie Yokouchi, Hirohiko Goto, Ken Umehara, Hideyuki Yamada, Yuji Ishii, Alleviation of fatty liver in a rat model by enhancing N 1 -methylnicotinamide bioavailability through aldehyde oxidase inhibition, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2018.11.008, 507, 1-4, 203-210, 2018.12, Nonalcoholic fatty liver disease (NAFLD) has increased worldwide in recent years. NAFLD is classified into two types, nonalcoholic fatty liver (NAFL), with few complications, and nonalcoholic steatohepatitis (NASH), which leads to liver cirrhosis or cancer. This study was based on previous reports that N 1 -methylnicotinamide (MNA) can stabilise sirtuin 1 protein, leading to decreased lipid levels in the liver. We hypothesised that fatty liver improvement by MNA would be further enhanced by suppressing its rapid metabolism by aldehyde oxidase in the liver. To test this, hydralazine (HYD), a potent aldehyde oxidase inhibitor, was administered orally to NAFL model rats. Liver triglyceride (TG) levels in the model were nearly unchanged by administration of MNA alone. In contrast, TG levels were marked decreased in NAFL rats treated with a combination of MNA and HYD. In addition, TG levels were decreased even in NAFL rats treated with only HYD. These findings supported our hypothesis that maintaining MNA concentrations in the liver, by suppressing MNA metabolism, would at least partially ameliorate fatty liver.. |
| 28. | Yukiko Hattori, Tomoki Takeda, Arisa Nakamura, Kyoko Nishida, Yuko Shioji, Haruki Fukumitsu, Hideyuki Yamada, YUJI ISHII, The aryl hydrocarbon receptor is indispensable for dioxin-induced defects in sexually-dimorphic behaviors due to the reduction in fetal steroidogenesis of the pituitary-gonadal axis in rats, Biochemical Pharmacology, https://doi.org/10.1016/j.bcp.2018.05.008, 154, 213-221, (2018), 2018.05. |
| 29. | Renshi Li, Xuewei Peng, Yanliang Wu, Weichao Lv, Haifeng Xie, Yuji Ishii, Chaofeng Zhang, Exposure to PM2.5 during pregnancy causes lung inflammation in the offspring: mechanism of action of mogrosides., Ecotoxicology and Environmental Safety, https://doi.org/10.1016/j.ecoenv.2021.112955, 228, 112955-112955, (2021), 2021.11. |
| 30. | Takayuki Koga, Kie Inoue, Fuka Hirayama, Makoto Hiromura, Kiyonaga Fujii, Yuji Ishii, Masayo Hirao-Suzuki, Shuso Takeda, Akihisa Toda, Fumio Soeda , Dimethylglycine, a methionine metabolite, participates in the suppressive effect of methionine on 1-fluoro-2,4-dinitrobenzene-induced dermatitis, Biological and Pharmaceutical Bulletin, 10.1248/bpb.b23-00098, 2023.05. |
| 31. | Yuu Miyauchi, Akane Kimura, Madoka Sawai, Keiko Fujimoto, Yuko Hirota, Yoshitaka Tanaka, Shinji Takechi, Peter I Mackenzie, Yuji Ishii, Use of a Baculovirus-Mammalian Cell Expression-System for Expression of Drug-Metabolizing Enzymes: Optimization of Infection With a Focus on Cytochrome P450 3A4, Frontiers in Pharmacology, 10.3389/fphar.2022.832931, 13, 832931-832931, 2022.02. |
| 32. | Renshi Li, Xuewei Peng, Yanliang Wu, Weichao Lv, Haifeng Xie, Yuji Ishii, Chaofeng Zhang, Exposure to PM2.5 during pregnancy causes lung inflammation in the offspring: mechanism of action of mogrosides., Ecotoxicology and Environmental Safety, https://doi.org/10.1016/j.ecoenv.2021.112955, 228, 112955-112955, (2021), 2021.11. |
| 33. | Ming Yuan, Hiroe Sano, Takaaki Nishino, Hongbin Chen, Ren-shi Li, Yuki Matsuo, Kyoko Nishida, Takayuki Koga, Tomoki Takeda, Yoshitaka Tanaka, Yuji Ishii, alpha-Lipoic acid eliminates dioxin-induced offspring sexual immaturity by improving abnormalities in folic acid metabolism, Biochemical Pharmacology, 10.1016/j.bcp.2023.115490, 210, 115490, 2023.04. |
| 34. | Yuu Miyauchi, Akane Kimura, Madoka Esaki, Keiko Fujimoto, Yuko Hirota, Yoshitaka Tanaka, Shinji Takechi, Peter I Mackenzie, Yuji Ishii, Use of a Baculovirus-Mammalian Cell Expression-System for Expression of Drug-Metabolizing Enzymes: Optimization of Infection With a Focus on Cytochrome P450 3A4, Frontiers in Pharmacology, 10.3389/fphar.2022.832931, 13, 832931-832931, Article 832931, 2022.02. |
| 35. | Hiroyuki Mohri, Kazuko Mohri, Akinaga Gohda, Yuji Ishii, Rapid derivatization of phosphorus-containing amino acid herbicides in plasma and urine using microwave heating, Journal of Toxicological Sciences, 48, 1, 15-24, 2023.01, [URL]. |
| 36. | Tomoki Takeda, Yukiko Komiya, Takayuki Koga, Takumi Ishida, Yuji Ishii, Yasushi Kikuta, Michio Nakaya, Hitoshi Kurose, Takehiko Yokomizo, Takao Shimizu, Hiroshi Uchi, Masutaka Furue, Hideyuki Yamada, Dioxin-induced increase in leukotriene B4 biosynthesis through the aryl hydrocarbon receptor and its relevance to hepatotoxicity owing to neutrophil infiltration, JOURNAL OF BIOLOGICAL CHEMISTRY, 10.1074/jbc.M116.764332, 292, 25, 10586-10599, 2017.06, Dioxin and related chemicals alter the expression of a number of genes by activating the aryl hydrocarbon receptors (AHR) to produce a variety of disorders including hepatotoxicity. However, it remains largely unknown how these changes in gene expression are linked to toxicity. To address this issue, we initially examined the effect of 2,3,7,8-tetrachrolodibenzo-p-dioxin (TCDD), a most toxic dioxin, on the hepatic and serum metabolome in male pubertal rats and found that TCDD causes many changes in the level of fatty acids, bile acids, amino acids, and their metabolites. Among these findings was the discovery that TCDD increases the content of leukotriene B4 (LTB4), an inducer of inflammation due to the activation of leukocytes, in the liver of rats and mice. Further analyses suggested that an increase in LTB4 comes from a dual mechanism consisting of an induction of arachidonate lipoxygenase-5, a rate-limiting enzyme in LTB4 synthesis, and the down-regulation of LTC4 synthase, an enzyme that converts LTA4 to LTC4. The above changes required AHR activation, because the same was not observed in AHR knock-out rats. In agreement with LTB4 accumulation, TCDD caused the marked infiltration of neutrophils into the liver. However, deleting LTB4 receptors (BLT1) blocked this effect. A TCDD-produced increase in the mRNA expression of inflammatory markers, including tumor-necrosis factor and hepatic damage, was also suppressed in BLT1-null mice. The above observations focusing on metabolomic changes provide novel evidence that TCDD accumulates LTB4 in the liver by an AHR-dependent induction of LTB4 biosynthesis to cause hepatotoxicity through neutrophil activation.. |
| 37. | Ayumi Kurita, Yuu Miyauchi, Shin'Ichi Ikushiro, Peter I. Mackenzie, Hideyuki Yamada, Yuji Ishii, Comprehensive characterization of mouse UDP-glucuronosyltransferase (Ugt) belonging to the Ugt2b subfamily Identification of Ugt2b36 as the predominant isoform involved in morphine glucuronidation, Journal of Pharmacology and Experimental Therapeutics, 10.1124/jpet.117.240382, 361, 2, 199-208, 2017.05, UDP-Glucuronosyltransferases (UGTs) are classified into three subfamilies in mice: Ugt1a, 2b, and 2a. In the Ugt1a subfamily, Ugt1a1 and 1a6 appear to correspond to human UGT1A1 and 1A6. The mouse is an important animal for its use in investigations, but the substrate specificities of Ugt isoforms belonging to the 2b subfamily in mice remain largely unknown. To address this issue, we characterized the substrate specificity of all isoforms of the Ugt2b subfamily expressed in the mouse liver. The cDNAs of Ugt1a1, Ugt2a3, and all the Ugt2b isoforms expressed in the liver were reverse-transcribed from the total RNA of male FVB-mouse livers and then amplified. A baculovirus-Sf9 cell system for expressing each Ugt was established. Of all the Ugts examined, Ugt2b34, 2b36, and 2b37 exhibited the ability to glucuronidate morphine with Ugt2b36, the most active in this regard. Ugt1a1, but also Ugt2b34, 2b36, and 2b37 to a lesser extent, preferentially catalyzed the glucuronidation of 17b-estradiol on the 3-hydroxyl group (E3G). With these isoforms, E3G formation by Ugt1a1 was efficient; however, Ugt2b5 exhibited a preference for the 17b-hydroxyl group (E17G). Ugt2b1 and Ugt2a3 formed comparable levels of E3Gand E17G. Ugt2b1 and 2b5 were the only isoforms involved in chloramphenicol glucuronidation. As Ugt2b36 is highly expressed in the liver, it is most likely that Ugt2b36 is a major morphine Ugt inmouse liver. Regarding E3G formation,Ugt1a1, like the human homolog, seems to play an important role in the liver.. |
| 38. | Tomoki Takeda, Yuki Matsuo, Kyoko Nishida, Akihisa Fujiki, Yukiko Hattori, Takayuki Koga, Yuji Ishii, Hideyuki Yamada, α-Lipoic acid potentially targets AMP-activated protein kinase and energy production in the fetal brain to ameliorate dioxin-produced attenuation in fetal steroidogenesis, Journal of Toxicological Sciences, 10.2131/jts.42.13, 42, 1, 13-23, 2017.01, Our previous studies demonstrated that treating pregnant rats with dioxins, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), targets the pituitary expression of luteinizing hormone (LH) to attenuate testicular steroidogenesis in fetuses, resulting in the imprinting of sexual immaturity of the offspring after reaching maturity. Furthermore, we found that although TCDD disturbs the tricarboxylic acid (TCA) cycle in the fetal hypothalamus, maternal co-treatment with α-lipoic acid (α-LA), a cofactor of the TCA cycle, restores a TCDD-produced reduction in the LH-evoked steroidogenesis as well as the TCA cycle activity in fetuses. However, the mechanism underlying the beneficial effect of α-LA remains to be fully elucidated. To address this issue, we compared the effect of α-LA with that of thiamine, another cofactor of the TCA cycle. As with α-LA, supplying thiamine to dams exposed to TCDD alleviates the reduced level of not only hypothalamic ATP but also pituitary LH and testicular steroidogenic protein in fetuses. However, thiamine had a much weaker effect than α-LA. In agreement with ATP attenuation, TCDD activated AMP-activated protein kinase (AMPK), a negative regulator of LH production, whereas the supplementation of α-LA allowed recovery from this defect. Furthermore, α-LA restored the TCDD-produced reduction in the pituitary expression of the receptor for gonadotropin-releasing hormone (GnRH), an upstream regulator of LH synthesis. These results suggest that α-LA rescues TCDD-produced attenuation during fetal steroidogenesis due not only to facilitation of energy production through the TCA cycle but also through suppression of AMPK activation, and the pituitary GnRH receptor may serve as a mediator of these effects.. |
| 39. | Tatsuro Nakamura, Naho Yamaguchi, Yuu Miyauchi, Tomoki Takeda, Yasushi Yamazoe, Kiyoshi Nagata, Peter I. Mackenzie, Hideyuki Yamada, YUJI ISHII, Introduction of an N-glycosylation site into UDP-glucuronosyltransferase 2B3 alters its sensitivity to cytochrome P450 3A1-dependent modulation., Front. Pharmacol., doi: 10.3389/fphar.2016.00427, 7, 427, 2016.10. |
| 40. | Ren-Shi Li, Tomoki Takeda, Takashi Ohshima, Hideyuki Yamada, YUJI ISHII, Metabolomic profiling of brain tissues of mouse chronically exposed to heroin., Drug Metab. Pharmacokinet., 10.1016/j.dmpk.2016.10.410, 32, 1, 108-111, (2017), 2016.10. |
| 41. | Takuya Uchikawa, Takahiro Kannno, Isao Maruyama, Nobuo Mori, Akira Yasutake, YUJI ISHII, Hideyuki Yamada, Demethylation of methylmercury and the enhanced production of formaldehyde in mouse liver., J. Toxicol. Sci., http://doi.org/10.2131/jts.41.479., 41, 479-487, 2016.07. |
| 42. | Yudai Kariyazono, Junki Taura, Yukiko Hattori, YUJI ISHII, Shizuo Narimatsu, Masatake Fujimura, Tomoki Takeda, Hideyuki Yamada, Effect of in utero exposure to endocrine disruptors on fetal steroidogenesis governed by the pituitary-gonad axis: a study in rats using different ways of administration. , J. Toxicol. Sci, http://doi.org/10.2131/jts.40.909, 40, 909-916, 2015.11. |
| 43. | Yuu Miyauchi, Kiyoshi Nagata, Yasushi Yamazoe, Peter I. Mackenzie, Hideyuki Yamada, YUJI ISHII, Suppression of cytochrome P450 3A4 function by UDP-glucuronosyltransferase (UGT) 2B7 through a protein-protein interaction: Cooperative roles of the cytosolic carboxyl-terminal domain and the luminal anchoring region of UGT2B7., Mol. Pharmacol., 88, 800-812, 2015.08. |
| 44. | Saki Kakizuka, Tomoki Takeda, Yuiko Komiya, Akihiko Koba, Uchi Hiroshi, Masutaka Furue, YUJI ISHII, Hideyuki Yamada, Dioxin-produced alteration in the profiles of fecal and urinary metabolomes: a change in bile acids and its relevance to toxicity., Biol. Pharm. Bull., 2015.06. |
| 45. | Ikuo Yamamiya, Kunihiro Yoshisue, ISHII YUJI, Yamada Hideyuki, Masato Chiba, Species variation in the enantioselective metabolism of tegafur to 5-fluorouracil. , J. Pharm. Pharmacol., 66, 1686-1697, 2014.12. |
| 46. | Junki Taura, Tomoki Takeda, Misaki Fujii, Yukiko Hattori, YUJI ISHII, Hiroaki Kuroki, Kiyomi Tsukimori, Uchi Hiroshi, Masutaka Furue, Hideyuki Yamada, 2,3,4,7,8-Pentachlorodibenzofuran is far less potent than 2,3,7,8-tetrachlorodibenzo-p-dioxin in disrupting the pituitary-gonad axis of the rat fetus. , Toxicol. Appl. Pharmacol., doi: 10.1016/j.taap.2014.09.001, 281, 1, 48-57, 2014.09. |
| 47. | Ikuo Yamamiya, Kunihiro Yoshisue, ISHII YUJI, Yamada Hideyuki, Masato Chiba, Effect of cytochrome P450 2A6 genetic polymorphism on the metabolic conversion of Tegafur to 5-fluorouracil and its enantioselectivity. , Drug Metab. Dispos., 42, 1485-1492, 2014.09. |
| 48. | Tomoki Takeda, Junki Taura, Yukiko Hattori, YUJI ISHII, Hideyuki Yamada, Dioxin-induced retardation of development through a reduction in the expression of pituitary hormones and possible involvement of an aryl hydrocarbon receptor in this defect: a comparative study using two strains of mice with different sensitivities to dioxin., Toxicol. Appl. Pharmacol., doi: 10.1016/j.taap.2014.04.022., 278, 3, 220-229, 2014.08. |
| 49. | Yukiko Hattori, Tomoki Takeda, Misaki Fujii, Junki Taura, YUJI ISHII, Hideyuki Yamada, Dioxin-induced fetal growth retardation: the role of a preceding attenuation in the circulating level of glucocorticoid., Endocrine, 2014.03. |
| 50. | Tomoki Takeda, Misaki Fujii, Yukiko Hattori, Midori Yamamoto, Takao Shimazoe, YUJI ISHII, Masaru Himeno, Hideyuki Yamada, Maternal Exposure to Dioxin Imprints Sexual Immaturity of the Pups through Fixing the Status of the Reduced Expression of Hypothalamic Gonadotropin-Releasing Hormone, Mol Pharmacol, http://dx.doi.org/10.1124/mol.113.088575, 85, 1, 74-82, 2014.01. |
| 51. | Ikuo Yamamiya, Kunihiro Yoshisue, ISHII YUJI, Yamada Hideyuki, Ken-ichiro Yoshida, Enantioselectivity in the cytochrome P450-dependent conversion of tegafur to 5-fluorouracil in human liver microsomes, Pharmacology Research & Perspectives, doi: 10.1002/prp2.9, 1, 1, e00009, 2013.11. |
| 52. | YUJI ISHII, Hiroki Koba, Kousuke Kinoshita, Toshiya Oizaki, Yuki Iwamoto, Shuso Takeda, Yuu Miyauchi, Yoshio Nishimura, Natsuki Egoshi, Futoshi Taura, Satoshi Morimoto, Shin'ichi Ikushiro, Kiyoshi Nagata, Yasushi Yamazoe, Peter I. Mackenzie, Hideyuki Yamada, Alteration of the Function of the UDP-Glucuronosyltransferase 1A Subfamily by Cytochrome P450 3A4: Different Susceptibility for UGT Isoforms and UGT1A1/7 Variants, Drug Metabolism and Disposition, doi:10.1124/dmd.113.054833, 2013.11. |
| 53. | Sayuri Tsujimoto, Takumi Ishida, Takeda Tomoki, ISHII YUJI, Yuko Onomura, Tsukimori Kiyomi, Takechi Shinji, Yamaguchi Tadatoshi, Uchi Hiroshi, Suzuki O. Satoshi, Yamamoto Midori, Himeno Masaru, Yamada Hideyuki, Selenium-binding protein 1: Its physiological function, dependence on aryl hydrocarbon receptors, and role in wasting syndrome by 2,3,7,8-tetrachlorodibenzo-p-dioxin., Biochimica et Biophysica Acta, doi:pii: S0304-4165(13)00086-X. 10.1016/j.bbagen.2013.03.008., 1830, 6, 3616-3624, 2013.05. |
| 54. | YUJI ISHII, Kie An, Yoshio Nishimura, Hideyuki Yamada, ATP Serves as an Endogenous Inhibitor of UDP-Glucuronosyltransferase (UGT): A New Insight into the 'Latency' of UGT, Drug Metabolism and Disposition, doi:10.1124/dmd.112.046862, 40, (11), 2081-2089, 2012.11. |
| 55. | YUJI ISHII, Naoko Iida, Yuu Miyauchi, Hideyuki Yamada, Inhibition of morphine glucuronidation in the liver microsomes of rats and humans by monoterpenoid alcohols, Biological & Pharmaceutical Bulletin, 35, 10, 1811-1817, 2012.10. |
| 56. | Koga T, Ishida T, Takeda T, Ishii Y, Uchi H, Tsukimori K, Yamamoto M, Himeno M, Furue M and Yamada H, Restoration of Dioxin-Induced Damage to Fetal Steroidogenesis and Gonadotropin Formation by Maternal Co-treatment with α-Lipoic Acid. , PLoS ONE, 10.1371/journal.pone.0040322 , 7, 7, e40322 , 2012.07. |
| 57. | Eyanagi R, Toda A, Imoto M, Uchiyama H, Ishii Y, Kuroki H, Kuramoto Y, Soeda
S, Shimeno H. , Covalent binding of nitroso-sulfonamides to glutathione S-transferase in guinea pigs with delayed type hypersensitivity. , Int. Immunopharmacol., 12, 4, 694-700, 2012.04. |
| 58. | Takeda T, Fujii M, Taura J, Ishii Y, Yamada H. , Dioxin Silences Gonadotropin Expression in Perinatal Pup by Inducing Histone Deacetylase: a New Insight into the Mechanism for the Imprinting of Sexual Immaturity by Dioxin., J. Biol. Chem., 287, 18440-18450, 2012.04. |
| 59. | Takeda T, Yamamoto M, Himeno M, Takechi S, Yamaguchi T, Ishida T, Ishii Y, Yamada H, 2,3,7,8-Tetrachlorodibenzo-p-dioxin potentially attenuates the gene expression of pituitary gonadotropin β-subunits in a fetal age-specific fashion: A comparative study using cultured pituitaries. , J. Toxicol. Sci., 36, 221-229, 2011.06. |
| 60. | Ishida T, Matsumoto Y, Takeda T, Koga T, Ishii Y, Yamada H, Distribution of 14C-2,3,7,8-tetrachlorodibenzo-p-dioxin to the brain and peripheral tissues of fetal rats and its comparison with adults., J. Toxicol. Sci., 35: 563-569 (2010)., 2010.08. |
| 61. | Matsumoto Y, Ishida T, Takeda T, Koga T, Fujii M, Ishii Y, Fujimura Y, Miura D, Wariishi H, Yamada H, Maternal exposure to dioxin reduces hypothalamic but not pituitary metabolome in fetal rats: a possible mechanism for a fetus-specific reduction in steroidgenesis., J. Toxicol. Sci., 35: 365-373 (2010)., 2010.06. |
| 62. | Nurrochmad A, Ishii Y, Nakanoh H, Inoue T, Horie T, Sugihara K, Ohta S, Taketomi A, Maehara Y, Yamada H, Activation of Morphine Glucuronidation by Fatty Acyl-CoAs and Its Plasticity: A Comparative Study in Humans and Rodents Including Chimeric Mice Carrying Human Liver, Drug Metabolism and Pharmacokinetics, 25, 3, 262-273, 2010.06. |
| 63. | Takeda T, Matsumoto Y, Koga T, Mutoh J, Nishimura Y, Shimazoe T, Ishii Y, Ishida T, Yamada H, Maternal exposure to dioxin disrupts gonadotropin production in fetal rats and imprints defects in sexual behavior. , J. Pharmacol. Exp. Ther., 329(3): 1091-1099. , 2009.06. |
| 64. | Ishida T, Takeda T, Koga T, Yahata M, Ike A, Kuramoto C, Taketoh J, Hashiguchi I, Akamine A, Ishii Y, Yamada H, Attenuation of 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity by resveratrol: a comparative study with different routes of administration, Biol. Pharm. Bull. , 32(5): 876-881. , 2009.05. |
| 65. | Ishida T., Sakai Y., Ishii Y., Furue M., Yamada H., The accelerated excretion of 2,3,4,7,8-pentachlorodibenzofuran by Cholebine., Fukuoka Igaku Zasshi, 100, 5, 210-216, 2009.05. |
| 66. | Takumi Ishida, Tomoki Takeda, Takayuki Koga, Masahiro Yahata, Ayako Ike, Chihiro Kuramoto, Junko Taketoh, Isamu Hashiguchi, Akifami Akamine, Yuji Ishii, Hideyuki Yamada, Attenuation of 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity by resveratrol: A comparative study with different routes of administration, Biological and Pharmaceutical Bulletin, 10.1248/bpb.32.876, 32, 5, 876-881, 2009.05, The activation of aryl hydrocarbon receptor with 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) is known to be antagonized by co-treatment with resveratrol. However, such a protective effect has been suggested from studies using subcutaneous injection of this polyphenol. To evaluate the practical usefulness of resveratrol, this study examined the protective effect of oral resveratrol on the sub-acute toxic effects of TCDD in C57BL/6J mice. A TCDD-induced wasting syndrome was not alleviated by treating mice for 28 d with oral resveratrol. However, subcutaneous injection of resveratrol for 5 d significantly improved the symptoms. Neither oral nor subcutaneous administration of resveratrol alleviated TCDD-induced hepatomegaly and thymic atrophy. Steatosis produced by TCDD was markedly counteracted by co-treatment with oral resveratrol, whereas resveratrol injected subcuta- neously had no effect. The reason for the lack of protective effect via the latter dosing route was assumed to be due to the minor accumulation of hepatic lipids 5 d after TCDD treatment. To clarify the mechanisms, the activity of ethoxyresorufin O-deethylase and the content of thiobarbituric acid-reactive substances in the liver were measured. Both indices increased by TCDD treatment were significantly suppressed by subcutaneous injection of resveratrol. In contrast, oral resveratrol failed to rescue them. In agreement with the greater protective effects of subcutaneously-injected resveratrol, pharmacokinetic studies indicated that the area under the curve extrapolated to infinity (AUC«,) was 8.2-times greater following subcutaneous injection compared with oral administration. These data suggest that 1) oral resveratrol is attractive candidate as an agent capable of combating dioxin toxicity and 2) increasing the bioavailability of this polyphenol enhances its protective effect. © 2009 Pharmaceutical Society of Japan.. |
| 67. | Takeda S, Ishii Y, Iwanaga M, Nurrochmad A, Ito Y, Mackenzie PI, Nagata K, Yamazoe Y, Oguri K, Yamada H. , Interaction of Cytochrome P450 3A4 and UDP-Glucuronosyltransferase 2B7: Evidence for Protein-Protein Association and Possible Involvement of CYP3A4 J-Helix in the Interaction. , Molecular Pharmacology, 75(4); 956-964. , 2009.04. |
| 68. | Ishida, T., Kawakami, M., Baba, H., Yahata, M., Mutoh, J., Takeda, S., Fujita, H., Tanaka. Y., Ishii, Y., & Yamada, H., Proteasome affects the expression of aryl hydrocarbon receptor-regulated proteins. Environ Pharmacol Toxicol., 2008; 26(3): 348-354. , Enviromental Pharmacology and Toxicology, 26(3): 348-354, 2008.11. |
| 69. | Ishida, T., Ishizaki, M., Tsutsumi, M., Ishii, Y., & Yamada, H., Piperine, a peper ingredient, improves the hepatic increase in free fatty acids caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin, Journal of Health Science, 54 (5), 551-558., 2008.07. |
| 70. | YUJI ISHII, Megumi Iwanaga, Yoshio Nishimura, Shuso Takeda, Shin'ichi Ikushiro, Kiyoshi Nagata, Yasushi Yamazoe, Peter I. Mackenzie, Yamada, H., Protein-protein interactions between rat hepatic cytochromes P450 (P450s) and UDP-glucuronosyltransferases (UGTs): Evidence for the functionally active UGT in P450-UGT complex., Drug Metabolism and Pharmacokinetics, http://doi.org/10.2133/dmpk.22.367, 22, 5, 367-376, 2007.10, [URL]. |
| 71. | Nishimura Y, Maeda S, Ikushiro, S., Mackenzie PI, Ishii Y, and Yamada, H., , Inhibitory effects of adenine nucleotides and related substances on UDP-glucuronosyltransferase: structure-effect relationships and evidence for an allosteric mechanism. , Biochim. Biophys. Acta, 1770(11):1557-1566. , 2007.10. |
| 72. | Matsuda K, Fukuzawa T, Ishii Y, Yamada H, Color reaction of 3,4-methylenedioxyamphetamines with chromotropic acid: its improvement and application to the screening of seized tablets. , Forensic Toxicology, 25: 37-40, 2007.06. |
| 73. | Taketoh J, Mutoh J, Ogishima T, Takeda S, Ishii Y, Ishida T, and Yamada H, Suppression of fetal testicular cytochrome P450 17 by maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin: a mechanism involving initial injury of gonadotropin synthesis in pituitary. , Life Science, 80: 1259-1267., 2007.03. |
| 74. | Matsuda K, Asakawa N, Iwanaga M, Gohda A, Fukushima S, Ishii Y, Yamada H, Conversion of gamma-hydroxybutyric acid to a fluorescent derivative: a method for screening, Forensic Toxicology, 24: 41-47., 2006.05. |
| 75. | Takeda S, Kitajima Y, Ishii Y, Mackenzie PI, Oguri K, Yamada H, Inhibition of UDP-Glucuronosyltransferase 2B7-Catalyzed Morphine Glucuronidation by Ketoconazole: Dual mechanisms involving A novel non-competitive mode, Drug Metabolism and Disposition, 34(8): 1277-1282, 2006.05. |
| 76. | Okamura K, Ishii Y, Ikushiro S, Mackenzie PI, Yamada H, Fatty acyl-CoA as an endogenous activator of UDP-glucuronosyltransferases, Biochemical and Biophysical Research Communications, 345: 1649-1656., 2006.05. |
| 77. | Hideyuki Yamada, Yuji Ishii, Midori Yamamoto, Kazuta Oguri, Induction of the hepatic cytochrome P4502B subfamily by xenobiotics: Research history, evolutionary aspect, relation to tumorigenesis, and mechanism, CURRENT DRUG METABOLISM, 7, 4, 397-409, 2006.05, The cytochrome P450 belonging to the CYP2B subfamily has long been of great interest because it can be induced by xenobiotics. While a well known diagnostic ligand-receptor theory explains the induction of the CYP1A subfamily, the mechanism by which xenobiotics induce the CYP2B subfamily is not full), understood. Although the constitutive androstane receptor (CAR) undoubtedly plays a crucial role in the induction, many questions regarding the mechanism of CAR activation by xenobiotics have [lot yet been answered. It is a puzzle that many structurally-unrelated chemicals call increase the expression of the CYP2B subfamily. This may Support a mechanism(s) distinct from the signaling induced by ligand-rcceptor binding. Indeed, phenobarbital. a typical inducer, cannot associate with CAR. Thus. no one is able to answer a fundamental question: what is the initial target of xenobiotics to produce induced expression of CYP2B enzymes? In this review, we survey the research history of CYP2B induction, list the inducers reported so far, and discuss the mechanism of induction including the target site of inducers.. |
| 78. | Mutoh J, Taketoh J, Okamura K, Kagawa T, Ishida T, Ishii Y, Yamada H, Fetal Pituitary Gonadotropin as an Initial Target of Dioxin in Its Impairment of Cholesterol Transportation and Steroidogenesis in Rats, Endocrinology, 147: 927-936., 2006.02. |
| 79. | Takeda S, Ishii Y, Mackenzie PI, Nagata K, Yamazoe Y, Oguri K, Yamada H, Modulation of UDP-Glucuronosyltransferase 2B7 Function by Cytochrome P450s In Vitro: Differential Effects of CYP1A2, CYP2C9 and CYP3A4., Biological and Pharmaceutical Bulletin, 10.1248/bpb.28.2026, 28, 10, 2026-2027, 28: 2026-2027, 2005.10. |
| 80. | Eyanagi R, Toda A, Ishii Y, Saito H, Soeda S, Shimeno H, Shigematsu H, Antigenicity of sulfanilamide and its metabolites using fluorescent-labelled compounds, Xenobiotica, 10.1080/00498250500251533, 35, 9, 911-925, 35: 911 – 925., 2005.09. |
| 81. | Ishida T, Naito E, Mutoh J, Takeda S, Ishii Y, Yamada H, The plant flavonoid, quercetin, reduces some forms of dioxin toxicity by mechanism distinct from aryl hydrocarbon receptor activation, heat-shock protein induction and quenching oxidative stress., Journal of Health Science, 10.1248/jhs.51.410, 51, 4, 410-417, 51: 410 - 417., 2005.07. |
| 82. | Ishii Y, Akazawa D, Aoki Y, Yamada H, Oguri K, Suppression of carbonic anhydrase III mRNA level by an arylhydrocarbon receptor ligand in primary cultured hepatocytes of rat., Biological and Pharmaceutical Bulletin, 10.1248/bpb.28.1087, 28, 6, 1087-1090, 28: 1087 - 1090., 2005.07. |
| 83. | Ishida T, Kan-o S, Mutoh J, Takeda S, Ishii Y, Hashiguchi I, Akamine A, Yamada H, 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced change in intestinal function and pathology: evidence for the involvement of arylhydrocarbon receptor-mediated alteration of glucose transportation., Toxicology and Applied Pharmacology, 10.1016/j.taap.2004.09.014, 205, 1, 89-97, 205: 89 - 97., 2005.07. |
| 84. | Takeda S, Ishii Y, Iwanaga M, Mackenzie PI, Nagata K, Yamazoe Y, Oguri K, Yamada H, Modulation of UDP-Glucuronosyltransferase Function by Cytochrome P450: Evidence for the Alteration of UGT2B7-Catalyzed Glucuronidation of Morphine by CYP3A4, Molecular Pharmacology, 10.1124/mol.104.007641, 67, 3, 665-672, 67(3): 665-672., 2005.03. |
| 85. | Takumi Ishida, Miho Hori, Yuji Ishii, Kazuta Oguri, Hideyuki Yamada, Effects of dioxins on stress-responsive systems and their relevance to toxicity, Journal of Dermatological Science, Supplement, 10.1016/j.descs.2005.03.011, 1, 1, S105-S112, 2005.04, Background: Dioxins and related compounds, exemplified by 2,3,7,8-tetrachlorodibenzo-p-dioxin, are recognized as widespread, persistent and highly toxic environmental pollutants. Although numerous studies have been performed to clarify the mechanisms governing dioxin toxicity, these are not yet fully understood because of their complexity. In 1968, subacute poisoning by polychlorinated biphenyls, called 'Yusho', occurred in the southwest part of Japan. Although many of the Yusho patients appear to be free from any of the symptoms produced by the pollutant at present, they remain at high risk of dioxin toxicity because of the high concentrations present in the body. To date, no effective method for combating this toxicity has been developed. Objective: In this review, we summarize dioxin toxicity by focusing on the quenching systems of reactive oxygen species and chaperone proteins. In addition, the possibility of the development of protective and therapeutic treatments for dioxin toxicity is discussed. © 2004.. |
| 86. | Ishida T, Taketoh J, Nakatsune E, Kan-o S, Naito E, Takeda S, Mutoh J, Ishii Y, Yamada H, Curcumin anticipates the suppressed body weight gain with 2,3,7,8-tetrachloro-dibenzo-p-dioxin in mice, Journal of Health Science, 10.1248/jhs.50.474, 50, 5, 474-482, 50(5): 474-482 (Published online May 21, 2004), 2004.10. |
| 87. | Ishii Y, Miyoshi A, Maji D, Yamada H, Oguri K, Simultaneous expression of guinea pig UDP-glucuronosyltransferase 2B21 and 2B22 in COS-7 cells enhances UGT2B21-catalyzed chloramphenicol glucuronidation, Drug Metabolism and Disposition, 10.1124/dmd.32.10., 32, 10, 1057-1060, 32(10): 1057-1060, 2004.10. |
| 88. | Ishida T, Oshimo T, Nishimura A, Mutoh J, Ishii Y, Koga N, Yamada H, Hashiguchi I, Akamine A, Oguri K, Reducing the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin using the antiulcer drug, geranylgeranylacetone, Biological and Pharmaceutical Bulletin, 27(9):1397-1402 (Published on line July 12, 2004), 2004.09. |
| 89. | Taura K, Naito E, Ishii Y, Mori M, Oguri K, Yamada H, Cytochrome P450 1A1 (CYP1A1) inhibitor alpha-naphthoflavone interferes with UDP-glucuronosyltransferase (UGT) activity in intact but not in permeabilized hepatic microsomes from 3-methylcholanthrene-treated rats: Possible involvement of UGT-P450 interactions, Biological and Pharmaceutical Bulletin, 10.1248/bpb.27.56, 27, 1, 56-60, 27(1):56-60, 2004.01. |
| 90. | Yamada H, Ishii K, Ishii Y, Ieiri I, Nishio S, Morita T, and Oguri K, Formation of highly analgesic morphine-6-glucuronide following physiologic concentration of morphine in human brain, Journal of Toxicological Science, 28(5):395-401., 2003.12. |
| 91. | Ishida T, Ishii Y, Yamada H, Oguri K, The induction of hepatic selenium-binding protein by aryl hydrocarbon (Ah)-receptor ligands in rats, Journal of Health Science, 10.1248/jhs.48.62, 48, 1, 62-68, 48 : 62-68, 2002.02. |
| 92. | Taguchi K, Kumagai Y, Endo A, Kikushima M, Ishii Y, Shimojo N, Phenanthraquinone affects endotherial nitric oxide synthase activity through modification of the thiol group: An alternative inhibition mechanism, Journal of Health Science, 47 : 571-574., 2001.12. |
| 93. | Ishii Y, Kato H, Hatsumura M, Ishida T, Ariyoshi N, Yamada H and Oguri K, Role of the dioxin-like toxic compound coplanar polychlorinated biphenyl, 3,3',4,4',5-pentachlorobiphenyl in reducing hepatic alcohol dehydrogenase levels in rats in vivo. , Journal of Health Science, 10.1248/jhs.47.575, 47, 6, 575-578, 2001.12. |
| 94. | Ishii, Y; Miyoshi, A; Watanabe, R; Tsuruda, K; Tsuda, M; Yamaguchi-Nagamatsu, Y; Yoshisue, K; Tanaka, M; Maji, D; Ohgiya, S; Oguri, K, Simultaneous expression of guinea pig UDP-glucuronosyltransferase 2B21 and 2B22 in COS-7 cells enhances UDP-glucuronosyltransferase 2B21-catalyzed morphine-6-glucuronide formation, Molecular Pharmacology, 60, 5, 1040-1048, 2001.11. |
| 95. | Ishii Y, Kato H, Hatsumura M, Ishida T, Ariyoshi N, Yamada H, Oguri K, Effect of a highly toxic coplanar polychlorinated biphenyl, 3,3',4,4',5-pentachlorobiphenyl on intermediary metabolism: reduced triose phosphate content in rat liver cytosol, Fukuoka Acta Medica, 92: 190-200., 2001.05. |
| 96. | Yamada H, Matsunaga H, Tsuji K, Matsumoto S, Yamamoto M, Ishii Y, Omiecinski CJ, Oguri K, Sequence analysis of CYP2B genes and catalytic profiles for P450s in Qdj:Sprague-Dawley rats that lack reponse to the phenobarbital-mediated induction of CYP2B2, Journal of pharmacology and experimental therapeutics, 295, 3, 986-993, 295 : 986-993., 2000.12. |
| 97. | Ikeda M, Ishii Y, Kato H, Akazawa D, Hatsumura M, Ishida T, Matsusue K, Yamada H, Oguri K, Suppression of carbonic anhydrase III in rat liver by a dioxin-related toxic compound, coplanar polychlorinated biphenyl, 3,3',4,4',5-pentachlorobiphenyl, Archives of biochemistry and biophysics, 10.1006/abbi.2000.1911, 380, 1, 159-164, 380 : 159-164., 2000.08. |
| 98. | Taura K, Yamada H, Hagino Y, Ishii Y, Mori M, Oguri K, Interaction between cytochrome P450 and other drug metabolizing enzymes: evidence for an association of CYP1A1 with microsomal epoxide hydrolase and UDP-glucuronosyltransferase, Biochemical and biophysical research communications, 10.1006/bbrc.2000.3076, 273, 3, 1048-1052, 273 : 1048-1052., 2000.07. |
| 99. | Ishii, Y; Hansen, AJ; Mackenzie, PI, Octamer transcription factor-1 enhances hepatic nuclear factor-1 alpha-mediated activation of the human UDP glucuronosyltransferase 2B7 promoter, Molecular Pharmacology, 57, 5, 940-947, 2000.05, [URL]. |
| 100. | Matsusue K, Ishii Y, Ariyoshi N, Oguri K, A highly toxic coplanar polychlorinated biphenyl compound suppresses Delta5 and Delta6 desaturase activities which play key roles in arachidonic acid synhthesis in rat liver, Chemical Research in Toxicology, 10.1021/tx990104r, 12, 12, 1158-1165, 12 : 1158-1165., 1999.12. |
| 101. | Ishida T, Fukuda A, Yoshioka Y, Maji D, Ishii Y, Oguri K, An Improved Method for the Purification and characterization of a 54 KDa Protein in Rat Liver Which has Recently been Identified as a Selenium-Binding Protein, Journal of Health Science, 45, 4, 203-208, 45/4,203-208, 1999.08. |
| 102. | Ishida T, Tasaki K, Fukuda A, Ishii Y, Oguri K, Induction of a Cytosolic 54 KDa protein in Rat Liver that is highly homologous to selenium-Binding Protein, Environmental Toxicology and Pharmacology, 10.1016/S1382-6689(98)00042-8, 6, 4, 249-255, 6 : 249-255., 1998.12. |
| 103. | Y Ishii, AJ Hansen, PI Mackenzie, Octamer transcription factor-1 enhances hepatic nuclear factor-1 alpha-mediated activation of the human UDP glucuronosyltransferase 2B7 promoter, MOLECULAR PHARMACOLOGY, 57, 5, 940-947, 2000.05, The human UDP glucuronosyltransferase, UGT2B7, is expressed in the liver and gastrointestinal tract, where it catalyzes the glucuronidation of steroids and bile acids. In this study, the UGT2B7 gene was isolated and its proximal promoter was analyzed. The UGT2B7 gene consists of 6 exons and extends over 16 kilobases (kb). It does not contain a canonical TATA box but has a region (-2 to -40) adjacent to the transcription start site that binds nuclear proteins. This region contains a consensus hepatic nuclear factor-1 alpha (HNF1 alpha)-binding site and an overlapping AT-rich segment. Varying lengths of the UGT2B7 gene promoter, with and without these sites, were fused to the firefly luciferase reporter gene and transfected into HepG2 cells. UGT2B7 promoter activity with the HNF1/AT-rich element was stimulated by cotransfection with HNF1 alpha. Additional activation was observed when HNF1 alpha and octamer transcription factor-1 (Oct-1) were cotransfected simultaneously. However, Oct-1 alone did not stimulate promoter activity and did not bind to the promoter in the absence of HNF1 alpha. Deletion of the HNF1/AT-rich region, or mutations in this region, abolished UGT2B7 gene promoter activity and prevented HNF1 alpha-mediated increases in promoter activity. The presence of HNF1 alpha and octamer transcription factor-1 (Oct-1) in the protein complex that bound to the HNF1/AT-rich region was demonstrated by gel shift analyses with antibodies specific to HNF1 alpha and Oct-1 protein. These results strongly suggest that the liver-enriched factor HNF1 alpha binds to, and activates, the UGT2B7 gene promoter and that the ubiquitous transcription factor, Oct-1, enhances this activation by directly interacting with HNF1 alpha. This interaction between HNF1 alpha and Oct-1 may fine-tune UGT2B7 expression.. |
| 104. | MATSUSUE K, ISHII Y, ARIYOSHI N, OGURI K, A highly toxic PCB produces unusual changes in the fatty acid composition of rat liver (共著), Toxicology Letters, 10.1016/S0378-4274(97)03881-2, 91, 2, 99-104, 1997.04. |
| 105. | H Fujisaki, M Mise, Y Ishii, H Yamada, K Oguri, Strychnine and brucine as the potent inducers of drug metabolizing enzymes in rat liver: different profiles from phenobarbital on the induction of cytochrome P450 and UDP-glucuronosyltransferase., The Journal of pharmacology and experimental therapeutics, 268, 2, 1024-31, 1994.02, The inducing activities of two alkaloids, strychnine and brucine, on the hepatic drug metabolizing enzymes were studied in rats. Administration of strychnine in the drinking water to rats significantly increased the hepatic microsomal activities of benzphetamine N-demethylation, strychnine 2-hydroxylation and testosterone hydroxylations at positions 16 alpha and 16 beta. These results together with that of immunostaining of microsomal proteins revealed that strychnine is a potent inducer of CYP2B1 and 2B2. The comparable induction of CYP2B1/2 was observed by brucine treatment with less toxic effect. Although this inducer increased CYP2B cytochrome P450s (P450s) to the maximum levels after 4 consecutive days of administration, the maximal increase by strychnine was attained after 3 days of administration. Immunoblotting experiment suggested that significant proteolysis of CYP2B1 occurs during treatment by strychnine and brucine. These alkaloids exhibited no ability to induce the activities of testosterone hydroxylations at positions 2 alpha, 6 beta and 7 alpha, benzo[a]pyrene 3-hydroxylation and aniline hydroxylation. In addition to the CYP2B P450, strychnine and brucine induced glutathione S-transferase toward 1-chloro-2,4-dinitrobenzene and UDP-glucuronosyltransferase toward 4-nitrophenol. On the other hand, the glucuronidations of 4-hydroxybiphenyl and morphine were not enhanced by alkaloid treatments. These results indicated that strychnine and brucine cause phenobarbital-like induction of the P450 enzyme, but show a different profile from phenobarbital in the induction of UDP-glucuronosyltransferase.. |
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