Cytochrome P450 1A1, 2C9, 2C19, and 3A4 Polymorphisms Account for Interindividual Variability of Toxicological Drug Metabolism in Cynomolgus Macaques

Abstract

Cytochromes P450 (P450s) and their genetic variants in humans are important drug-metabolizing enzymes partly accounting for interindividual variations in drug metabolism and toxicity. However, these genetic variants in P450s have not been fully investigated in cynomolgus macaques, a nonhuman primate species widely used in toxicological studies. In this study, genetic variants found in cynomolgus CYP1A1, CYP2C9 (formerly CYP2C43), CYP2C19 (CYP2C75), and CYP3A4 (CYP3A8) were assessed on functional importance. Resequencing of CYP1A1 in cynomolgus macaques found 18 nonsynonymous variants, of which M121I and V382I were located in SRSs, domains potentially important for P450 function. By further analyzing these two variants, V382I was significantly associated with lower drug-metabolizing activities in the liver for the heterozygotes than the wild types. Similarly, the heterozygotes or homozygotes of CYP2C9 variants (A82V and H344R) and CYP2C19 variant (A490V) showed significantly lower drug-metabolizing activities in the liver than the wild types. Moreover, the homozygotes of CYP3A4 variant (S437N) showed significantly higher activities than the wild type in the liver. Kinetic analyses using recombinant proteins revealed that CYP2C9 variants (A82V and H344R) showed substantially lower K s values than the wild type, although CYP1A1 variant (V382I) showed kinetic parameters similar to the wild type. Likewise, CYP2C19 variant (A490V) showed substantially a lower V max/K m value than the wild type, whereas CYP3A4 variant (S437N) showed a higher V max/K m value than the wild type. These results suggest the toxicologically functional importance of CYP2C9 variants (A82V and H344R), CYP2C19 variant (A490V), and CYP3A4 variant (S437N) for hepatic drug metabolism in cynomolgus macaques.

Mitragyna speciosa: Clinical, Toxicological Aspects and Analysis in Biological and Non-Biological Samples

“…The same authors have described that mitragynine was extensively metabolized in liver microsomes primarily to O -demethylated and mono-oxidated metabolites. Due to these cytochrome-related genetic variations in humans, these enzymes will partly account for inter-individual differences in drug metabolism and toxicity [43].…”

A Critical Review of the Neuropharmacological Effects of Kratom: An Insight from the Functional Array of Identified Natural Compounds

“…Mitragynine was substantially degraded in liver microsomes, largely to O-demethylated and mono-oxidated metabolites, according to Kamble et al [101]. Some other investigations that assessed the effects of kratom on human recombinant CYP450 enzyme activity have confirmed that these enzymes partially account for inter-individual variability in drug metabolism and toxicity due to cytochrome-related genetic variants in humans [100,102]. This finding implies that mitragynine should be administered concurrently with herbal or contemporary medications that follow the same metabolic pathway as herb-drug interactions [103].…”

Genetics and Extracellular Vesicles of Pediatrics Sleep Disordered Breathing and Epilepsy

“…Several studies have been focused on drug–drug interactions and genetic polymorphisms including CYP2D6, CYP2C9 and CYP2C19 activities [92,93,94]. In particular, CYP2C19 enzyme is involved in the hepatic metabolism of drugs such as chemotherapeutic agents (cyclophosphamide), anti-epileptics (S-mephenytoin, diazepam, phenobarbitone), antiplatelets (clopidogrel), proton pump inhibitors (omeprazole, pantoprazole, lansoprazole, rabeprazole), antivirals (nelfinavir), and antidepressants (amitriptyline, clomipramine) [95,96,97].…”