薬物代謝酵素複合体の解析
キーワード：P450; UGT; グルクロン酸抱合, 衛生薬学、薬物代謝、環境薬学
2003.04.

ダイオキシン類による毒性発現機構に関する研究
キーワード：ダイオキシン類; ポリ塩化ビフェニル; 油症
2003.04.

主要著書

1.	Amit V. Pandey, Colin J. Henderson, Yuji Ishii, Michel Kranendonk, Wayne L. Backes, Ulrich M. Zanger, Role of Protein-Protein Interactions in Metabolism: Genetics, Structure, Function, Frontiers Media SA, 2018.01.
2.	YUJI ISHII, Yuu Miyauchi, Hideyuki Yamada, Chapter 18: Cytochrome P450-Dependent Change in UDP-Glucuronosyltransferase Function and Its Reverse Regulation in "Fifty Years of Cytochrome P450 Research", Springer Japan, 2014.06.
3.	石井祐次、小栗一太, 油症発症機構に関する生化学的研究 油症研究-30年の歩み-, 九州大学出版, pp. 143-162 （単行本）分担執筆, 2000.01.

主要原著論文

1.	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.
2.	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.
3.	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..
4.	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, [URL].
5.	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..
6.	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..
7.	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, [URL], 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..
8.	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, [URL], 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..
9.	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, [URL], 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..
10.	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, [URL], 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..
11.	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.
12.	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, [URL].
13.	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.
14.	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..
15.	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, [URL], 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..
16.	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, [URL], 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..
17.	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, [URL].
18.	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.
19.	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.
20.	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.
21.	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.
22.	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.
23.	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.
24.	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.
25.	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.
26.	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.
27.	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.
28.	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].
29.	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.
30.	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.
31.	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.
32.	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.
33.	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.
34.	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.
35.	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.
36.	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.
37.	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.
38.	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.
39.	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, [URL].

主要総説, 論評, 解説, 書評, 報告書等

1.	Yuu Miyauchi, Shinji Takechi and Yuji Ishii, Functional interaction between cytochrome P450 and UDP-glucuronosyltransferase on the endoplasmic reticulum membrane: one of post-translational factors which possibly contributes to their inter-individual differences, Biological & Pharmaceutical Bulletin, https://doi.org/10.1248/bpb.b21-00286, 44(11): 1635-1644 (2021), 2021.11.
2.	Frue Masutaka, ISHII YUJI, Tsukimori Kiyomi, Tsuji Gaku, Aryl Hydrocarbon Receptor and Dioxin-Related Health Hazards-Lessons from Yusho., Int J Mol Sci, doi: 10.3390/ijms22020708., 22(2):E708, 2021.01.
3.	ISHII YUJI, Arief Nurrochmad, Yamada, H., Modulation of UDP-glucuronosyltransferase activity by endogenous compounds, Drug Metabolism and Pharmacokinetics, 2010.04, [URL].
4.	ISHII YUJI, Shuso Takeda, Yamada, H., Modulation of UDP-glucuronosyltransferase activity by protein-protein association, Drug Metabolism Reviews, 2010.01, [URL].

主要学会発表等

所属学会名

学協会役員等への就任

学会大会・会議・シンポジウム等における役割

学会誌・雑誌・著書の編集への参加状況

学術論文等の審査

海外渡航状況, 海外での教育研究歴

外国人研究者等の受入れ状況