Regional Distribution of Cytochrome P450 mRNA Expression in the Liver and Small Intestine of Cynomolgus Monkeys

Abstract

The cynomolgus monkey is used to study drug metabolism because of its evolutionary closeness to humans. Despite their importance, regional distribution of cytochrome P450 (CYP) enzymes including CYP3As in the liver and small intestine, the major sites of drug metabolism, has not been fully investigated in cynomolgus monkeys. In this study, we measured mRNA expression levels of 14 CYPs in the CYP1, 2, and 3 subfamilies, including orthologs of human CYP3A4 and CYP3A5, in the liver and small intestine of cynomolgus monkeys. Expression levels of each CYP mRNA in various regions of the liver were quantified and comparisons were made between the right lobe, quadrate lobe, left medial lobe, left lateral lobe, and caudate lobe and with four different sections of the right lobe. In the small intestine, the same mRNAs were measured in the duodenum and six different sections from the proximal jejunum to the distal ileum. Expression levels of the CYP mRNAs were not substantially different between liver samples, but varied between the different sections of the small intestine, including CYP3A4. These results suggest that analysis of distinct sections is required for a better understanding of cynomolgus monkey CYPs in the small intestine.

Qualitative De Novo Analysis of Full Length cDNA and Quantitative Analysis of Gene Expression for Common Marmoset (Callithrix jacchus) Transcriptomes Using Parallel Long-Read Technology and Short-Read Sequencing

“…5B), just as cynomolgus P450 3A4 gene is in cynomolgus intestine [40]. P450 3A4 is the most abundantly expressed P450 in human small intestine [42].…”

“…This gene was previously named P450 3A21 , but is referred to as P450 3A4 in this article. P450 3A4 gene is also abundantly expressed in cynomolgus macaque livers [40]. P450 3A4 is one of the most important drug-metabolizing enzymes because it is involved in the oxidation of more than half of all prescription drugs.…”

Species Difference between Cynomolgus Monkeys and Humans on Cytochromes P450 2D and 3A-Dependent Drug Oxidation Activities in Liver Microsomes

“…20) In small intestines of cynomolgus monkeys, mRNA expression of CYP2D17 was much lower than those of mfCYP3A4 and mfCYP3A5. 21) Therefore, the low bioavailability in monkeys might be caused by highly active P450 enzymes and/or broader substrate specificity of P450 3A. In addition, CYP3A5 mRNA levels were comparable between the liver and jejunum.…”

“…In addition, CYP3A5 mRNA levels were comparable between the liver and jejunum. 21) The monkey mf-CYP3A5 has a possibility to play a major role in the first-pass metabolism of P450 3A substrates.…”

Pitavastatin as an In Vivo Probe for Studying Hepatic Organic Anion Transporting Polypeptide-Mediated Drug–Drug Interactions in Cynomolgus Monkeys

“…Pitavastatin is also a substrate of efflux transporters and metabolic enzymes, such as P-gp, breast cancer resistance protein (BCRP), multidrug resistance-associated protein 2 (MRP2), CYP2C, and UGT in humans (Yamada et al, 2003;Hirano et al, 2005Hirano et al, , 2006Uno et al, 2007;Korzekwa et al, 2012). Also, mRNA expression of monkey orthologs of the transporters and the monkey CYP2C in the gastrointestinal tract of cynomolgus monkeys has been reported (Nakanishi et al, 2010;Utoh et al, 2012). Pitavastatin was also metabolized by CYP2C and UGT in monkeys, although a monkey-specific CYP2C isoform (CYP2C76) was shown to be involved in pitavastatin metabolism (Yamada et al, 2003;Uno et al, 2007).…”