Genetic variants of aldehyde oxidase (AOX) 1 in cynomolgus and rhesus macaques

Abstract

1. The cynomolgus macaque is a non-human primate species widely used in drug metabolism studies. Despite the importance of genetic polymorphisms in cytosolic aldehyde oxidase (AOX) 1 in humans, genetic variants have not been investigated in cynomolgus or rhesus macaques.

2. Genetic variants in AOX1 were identified and allele frequencies were assessed using the genomes of 24 cynomolgus and 8 rhesus macaques. The analysis identified 38 non-synonymous variants, some of which were unique to cynomolgus macaques (bred in Cambodia, Indochina, or Indonesia) or rhesus macaques, whereas many variants were shared by the two lineages.

3. Among the variants observed at relatively high frequencies, eight were selected for functional analysis. Recombinant P605L and V1338I AOX1 variants showed substantially lower phthalazine and carbazeran oxidation activities than the wild-type AOX1 protein.

4. In liver cytosolic fractions from cynomolgus and rhesus macaques genotyped for P605L and V1338I AOX1, groups of cytosolic fractions with P605L and/or V1338I AOX1 variants showed significantly lower phthalazine and carbazeran oxidation activities than the wild type.

5. These results indicate that AOX1 is polymorphic in cynomolgus and rhesus macaques, just as it is in humans. Further investigation is needed to reveal the functional significance of these AOX1 variants in drug metabolism.

Keywords:

• AOX1
• cynomolgus macaque
• rhesus macaque
• drug-metabolizing enzyme
• genetic variants

Acknowledgments

The authors thank Makiko Shimizu, Yusuke Kamiya, Kaito Banju, and Takanori Serizawa for their technical help. The authors also thank David Smallbones, who copyedited an early draft of this manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported in part by the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research 20K06434 (Y.U.) and 20K07164 (H.Y.)