| 4. |
Cytochromes P450 (CYP) are well known for their important roles in drug metabolism. A growing number of preclinical and clinical studies have demonstrated that the polymorphism of the CYP genes is responsible for overall outcomes of pharmacotherapy. Functionally important polymorphisms (e.g., single nucleotide polymorphism, SNP), have been identified in CYP1A2, 2A6, 1B1, 2C8, 2C9, 2C19, 2D6 and 2E1. Although CYP3A4 is involved in the metabolism of < 60% of clinically available drugs, it is generally accepted that most of the known SNPs in the coding and 5’-flanking regions are not the main determinants for the large inter-individual variability in the phenotypes. In order to resolve this issue, we recently introduced “allelic variation”, one of the epigenetic gene alterations, in which RNA expression level is different between the two alleles (i.e., paternal and maternal allele). There existed a definite correlation between the total CYP3A4 mRNA level and allelic expression ratio, the relative transcript level ratio derived from the two alleles. Individuals with a low expression ratio, exhibiting a large difference of transcript level between the two alleles, revealed extremely low levels of total hepatic mRNA, and thus low metabolic capability. These results present a new insight into the individualized CYP3A4-dependent pharmacotherapy and the importance of expression imbalance to human phenotypic diversity. In addition to allelic variations, we will describe recent SNP-based findings in human CYPs.. |
