Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima-city, Japan.
Shin Nippon Biomedical Laboratories, Ltd, Kainan, Japan.
Xenobiotica. 2021 Apr;51(4):494-499. doi: 10.1080/00498254.2021.1874564. Epub 2021 Jan 17.
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 () 1 in humans, genetic variants have not been investigated in cynomolgus or rhesus macaques.Genetic variants in 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.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.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.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.
食蟹猴是一种常用于药物代谢研究的非人类灵长类动物。尽管人类细胞色素 P450 单加氧酶 1（）中的遗传多态性非常重要，但尚未在食蟹猴或恒河猴中研究过遗传变异。本研究鉴定了中的遗传变异，并使用 24 只食蟹猴和 8 只恒河猴的基因组评估了等位基因频率。分析鉴定了 38 个非同义变异，其中一些变异仅存在于食蟹猴（在柬埔寨、印度支那或印度尼西亚繁殖）或恒河猴中，而许多变异存在于两个谱系中。在观察到的相对高频变异中，选择了 8 个进行功能分析。重组 P605L 和 V1338I AOX1 变体的邻苯二甲酰亚胺和卡巴唑氧化活性明显低于野生型 AOX1 蛋白。对 P605L 和 V1338I AOX1 基因型的食蟹猴和恒河猴肝胞质部分进行分析，结果显示，携带 P605L 和/或 V1338I AOX1 变体的胞质部分的邻苯二甲酰亚胺和卡巴唑氧化活性明显低于野生型。这些结果表明，AOX1 在食蟹猴和恒河猴中与人类一样存在多态性。需要进一步研究来揭示这些 AOX1 变体在药物代谢中的功能意义。
