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 AOX1variants in drug metabolism.

摘要

1. 食蟹猕猴是一种广泛用于药物代谢研究的非人类灵长类动物。尽管人类胞质醛氧化酶（AOX）1的遗传多态性很重要，但尚未在食蟹猴或猕猴中研究遗传变异。

2. 鉴定了AOX1的遗传变异，并使用24个食蟹猴和8个猕猴的基因组评估了等位基因频率。分析确定了38个非同义变体，其中一些是猕猴（在柬埔寨，印度支那或印度尼西亚繁殖）或恒河猴所特有的，而两个谱系共有许多变体。

3. 在以较高频率观察到的变体中，选择了八个进行功能分析。重组的P605L和V1338I AOX1变体显示出比野生型AOX1蛋白低得多的邻苯二甲嗪和碳青霉烷氧化活性。

4. 在针对P605L和V1338I AOX1基因型的食蟹猕猴和猕猴的肝细胞溶质组分中，具有P605L和/或V1338I AOX1变体的细胞溶质组分组显示出比野生型低得多的邻苯二甲酰肼和甲氧杂环丁烷氧化活性。

5. 这些结果表明，AOX1在猕猴和恒河猕猴中具有多态性，就像在人类中一样。需要进一步研究以揭示这些AOX1变体在药物代谢中的功能意义。