Macaque CYP2C76 Encodes Cytochrome P450 Enzyme Not Orthologous to Any Human Isozymes

Yasuhiro      Uno; Hideki      Fujino; Kazuhide      Iwasaki; Masahiro      Utoh

doi:10.2174/138920010791110854

Abstract

Cynomolgus monkey is used in the study of drug metabolism and toxicity due to its evolutionary closeness to human as compared with other non-human primate species. However, it has become certain that drug metabolism in monkeys is different than in humans. Such species differences have not been fully investigated at a molecular level largely due to the scarcity of information on drug-metabolizing enzyme genes. In cynomolgus monkey, we have identified cDNAs for 21 kinds of cytochromes P450 (CYPs), among which CYP2C76 does not correspond to any human CYP isozymes and is partly responsible for the difference in pitavastatin metabolism between cynomolgus monkey and human. In cynomolgus monkey CYP2C76, we identified numerous genetic variants including a null genotype. Heterozygotes for this null genotype are expected to be poor metabolizers in CYP2C76-mediated drug metabolism. To provide new clues to CYP2C76 function, here, we have taken advantage of sequence information that has been recently deposited to public databases to assess the presence of CYP2C76 orthologs in primate species. In this assessment, we found the CYP2C76 cDNA sequence in rhesus monkey, and a gene sequence highly homologous to cynomolgus monkey CYP2C76 in the marmoset and orangutan genomes, raising the possibility that CYP2C76 could also play a role in these primate species. This review paper gives an overview of CYP2C76 from isolation to molecular characterization, and its implication in drug metabolism.

Keywords: Cytochrome P450, cynomolgus monkey, rhesus monkey, primate, null allele, drug metabolism, pitavastatin, species difference