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

Yasuhiro Uno1, Makiko Shimizu2, Hiromi Yoda2

  • 1Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan.

Drug Metabolism and Pharmacokinetics
|November 14, 2018
PubMed

Insights

Genetic variations in the flavin-containing monooxygenase 3 (FMO3) enzyme were identified in cynomolgus and rhesus macaques. These polymorphisms impact drug metabolism, similar to findings in humans.

Area of Science:

  • Pharmacogenomics
  • Primate drug metabolism

Background:

  • Flavin-containing monooxygenase 3 (FMO3) is a key enzyme in metabolizing nitrogen- and sulfur-containing drugs.
  • Cynomolgus and rhesus macaques are vital non-human primate models for drug metabolism studies, sharing similarities with humans.
  • Genetic polymorphisms in human FMO3 are known to affect drug response, but have not been studied in macaques.

Purpose of the Study:

  • To investigate genetic polymorphisms in the FMO3 gene in cynomolgus and rhesus macaques.
  • To functionally characterize identified FMO3 variants and assess their impact on drug metabolism.
  • To determine if macaque FMO3 polymorphisms contribute to inter-individual variability in drug metabolism.

Main Methods:

  • Re-sequencing of the FMO3 gene in 64 cynomolgus and 32 rhesus macaques.
  • Heterologous expression of cynomolgus FMO3 variants in Escherichia coli for in vitro functional assays.
  • Enzymatic activity assays using methimazole and benzydamine as substrates.
  • Analysis of benzydamine N-oxygenation in liver microsomes from homozygous variant and wild-type macaques.

Main Results:

  • A total of 18 non-synonymous FMO3 variants were identified across both macaque species.
  • Nine variants were unique to cynomolgus macaques, with distinct distributions among Indochinese and Indonesian lineages.
  • Five variants were unique to rhesus macaques, including S504T at high allele frequencies.
  • The FMO3 R509H variant showed suppressed methimazole and benzydamine oxygenation.
  • Seven variants exhibited reduced benzydamine N-oxygenation, with FMO3 G530A and R417H showing significant reductions in homozygotes.

Conclusions:

  • Genetic polymorphisms in FMO3 exist in cynomolgus and rhesus macaques, analogous to humans.
  • Identified FMO3 variants significantly alter the enzyme's ability to metabolize drugs like benzydamine.
  • These macaque FMO3 polymorphisms contribute to the observed inter-animal variability in drug metabolism, reinforcing their utility as models.
Keywords:
Cynomolgus monkeyDrug-metabolizing activityGenetic variantsLiverRhesus monkey

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