遗传多态性对人 SULT1C4 同工酶对阿霉素磺化的影响。
Effects of genetic polymorphisms on the sulfation of doxorubicin by human SULT1C4 allozymes.
机构信息
Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo Health Science Campus, 3000 Arlington Avenue, Toledo, OH 43614, USA.
Department of Pharmacology, College of Pharmacy, University of Karbala, Furaiha Street, Karbala, 56001, Iraq.
出版信息
J Biochem. 2021 Oct 12;170(3):419-426. doi: 10.1093/jb/mvab055.
Doxorubicin is a chemotherapeutic drug widely utilized in cancer treatment. An enzyme critical to doxorubicin metabolism is the cytosolic sulfotransferase (SULT) SULT1C4. This study investigated the functional impact of SULT1C4 single nucleotide polymorphisms (SNPs) on the sulfation of doxorubicin by SULT1C4 allozymes. A comprehensive database search was performed to identify various SULT1C4 SNPs. Ten nonsynonymous SULT1C4 SNPs were selected, and the corresponding cDNAs, packaged in pGEX-2TK expression vector, were generated via site-directed mutagenesis. Respective SULT1C4 allozymes were bacterially expressed and purified by affinity chromatography. Purified SULT1C4 allozymes, in comparison with the wild-type enzyme, were analysed for sulphating activities towards doxorubicin and 4-nitrophenol, a prototype substrate. Results obtained showed clearly differential doxorubicin-sulphating activity of SULT1C4 allozymes, implying differential metabolism of doxorubicin through sulfation in individuals with distinct SULT1C4 genotypes.
阿霉素是一种广泛用于癌症治疗的化疗药物。细胞溶质磺基转移酶（SULT）SULT1C4 是阿霉素代谢的关键酶。本研究调查了 SULT1C4 单核苷酸多态性（SNP）对 SULT1C4 同工酶磺化阿霉素的功能影响。进行了全面的数据库搜索以鉴定各种 SULT1C4 SNP。选择了 10 个非同义 SULT1C4 SNP，并通过定点诱变生成了相应的 cDNA，包装在 pGEX-2TK 表达载体中。通过亲和层析从细菌中表达和纯化相应的 SULT1C4 同工酶。与野生型酶相比，分析了纯化的 SULT1C4 同工酶对阿霉素和 4-硝基苯酚（原型底物）的磺化活性。结果清楚地表明 SULT1C4 同工酶对阿霉素的磺化活性存在差异，这意味着具有不同 SULT1C4 基因型的个体通过磺化对阿霉素的代谢存在差异。
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