Non-synonymous genetic variants of flavin-containing monooxygenase 3 (FMO3) in cynomolgus macaques

摘要

Polymorphic human flavin-containing monooxygenase (FMO) 3 is an important drug-metabolizing enzyme for nitrogen- or sulfur-containing compounds. Cynomolgus macaques, a non-human primate species widely used in drug metabolism studies, have corresponding FMO3 molecular and enzymatic similarities to humans; however, genetic polymorphisms have not been investigated in macaques. In this study, re-sequencing of FMO3 in 64 cynomolgus and 32 rhesus macaques found a total of 18 non-synonymous variants. Nine variants were unique to cynomolgus macaques, of which 4 (including Q506K) were found only in Indochinese, 4 (including V299I, E348H, and G530A) only in Indonesian lineages, and one was common. Other five variants (including S504T at 10% allele frequencies) were unique to rhesus macaques. By functional characterization using cynomolgus FMO3 proteins heterologously expressed in Escherichia coli , FMO3 R509H variant appeared to suppress methimazole and benzydamine S - or N -oxygenations. Seven variants showed substantially lower benzydamine N -oxygenation as compared with wild-type FMO3 protein. Further analysis indicated that two of these variants, FMO3 G530A and R417H, showed significantly lower benzydamine N -oxygenation in liver microsomes of the homozygotes as compared with wild-type animals. Therefore, inter-animal variability of FMO3-dependent drug metabolism is at least partly accounted for by genetic polymorphisms in cynomolgus and rhesus macaques, similar to humans.