Genetic Variants of Glutathione S-Transferase GSTT1 and GSTT2 in Cynomolgus Macaques: Identification of GSTT Substrates and Functionally Relevant Alleles.
Genetic Variants of Glutathione S-Transferase GSTT1 and GSTT2 in Cynomolgus Macaques: Identification of GSTT Substrates and Functionally Relevant Alleles.
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食蟹猴中谷胱甘肽 S-转移酶 GSTT1 和 GSTT2 的遗传变异：GSTT 底物和功能相关等位基因的鉴定。
DOI：
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发表时间：
2018
影响因子：
4.1
通讯作者：
H. Yamazaki
中科院分区：
文献类型：
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作者：
Y. Uno;N. Murayama;Masami Kato;Saki Tanaka;Tomoko Ohkoshi;H. Yamazaki
谷胱甘肽S-转移酶（GST）是重要的药物代谢酶，结合内源性和外源性化合物的家族。遗传多态性导致人类人口中GST活性的个体间变异性。特别是，人类GSTT1和GSTT2无效等位基因与毒性和来自化学物质的各种癌症有关。 Cynomolgus Macaque是一种非人类灵长类动物，广泛用于药物代谢研究，具有GST与人类直系同源物的分子和酶促相似性。但是，尚未在该物种中研究遗传多态性。在这项研究中，在64个cynomolgus和32颗恒河猕猴中重新纠正GSTT1和GSTT2，发现GSTT1的GSTT1和15个非同义词的非同义变体和15个非单词变体的GSTT2变体。这些GSTT变体中的一些在印度尼西亚和印度尼西亚cynomolgus猕猴和恒河猕猴中分布不同。为了分析GSTT变体的功能相关性，确定1-碘己烷和二溴甲烷为cynomolgus GSTT1和GSTT2的合适底物。但是，结合活性与GSTT蛋白水平在cynomolgus肝样品中进行了免疫化学量化大致相关，没有统计学意义，这意味着GST遗传变异的贡献。在鉴定出的GSTT1变体中，携带R76C和D125G突变的动物显示出对二纤维甲烷的共轭活性低于肝胞质级分中野生型的动物。此外，重组R76C/D125G和D125G GSTT变体蛋白显示出比野生型蛋白的1-碘己烷或二溴甲烷共轭活性的明显低。因此，依赖GSTT的药物代谢的动物间可变性至少部分由GSTT1以及cynomolgus和Rhesus猕猴中的GSTT2变体所解释。
Glutathione S-transferase (GST) is a family of important drug-metabolizing enzymes, conjugating endogenous and exogenous compounds. Genetic polymorphisms result in the inter-individual variability of GST activity in humans. Especially, human GSTT1 and GSTT2 null alleles are associated with toxicity and various cancers derived from chemicals. Cynomolgus macaque, a nonhuman primate species widely used in drug metabolism studies, has molecular and enzymatic similarities of GSTs to the human orthologs; however, genetic polymorphisms have not been investigated in this species. In this study, resequencing of GSTT1 and GSTT2 in 64 cynomolgus and 32 rhesus macaques found 15 nonsynonymous variants and 1 nonsense variant for GSTT1 and 15 nonsynonymous variants for GSTT2. Some of these GSTT variants were distributed differently in Indochinese and Indonesian cynomolgus macaques and rhesus macaques. For analysis of functional relevance of the GSTT variants, 1-iodohexane and dibromomethane were determined to be suitable substrates for cynomolgus GSTT1 and GSTT2. However, the conjugation activities were roughly correlated with GSTT protein levels immunochemically quantified in cynomolgus liver samples with no statistical significances, implying the contributions of the GST genetic variants. Among the GSTT1 variants identified, the animals carrying R76C and D125G mutations showed lower conjugation activities toward dibromomethane than those of the wild-type in liver cytosolic fractions. Moreover, the recombinant R76C/D125G and D125G GSTT variant proteins showed significantly lower 1-iodohexane or dibromomethane conjugation activities than those of the wild-type protein. Therefore, inter-animal variability of GSTT-dependent drug metabolism is at least partly accounted for by GSTT1 and possibly GSTT2 variants in cynomolgus and rhesus macaques.
影响因子：
4.1
作者：
KOLM, RH;DANIELSON, UH;MANNERVIK, B
通讯作者：
MANNERVIK, B