Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo Health Science Campus, Toledo, OH, 43614, USA; Department of Pharmacology, College of Pharmacy, University of Kufa, Najaf, Iraq.
Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo Health Science Campus, Toledo, OH, 43614, USA; Department of Pharmacology, College of Pharmacy, University of Karbala, Karbala, Iraq.
Arch Biochem Biophys. 2018 Jun 15;648:44-52. doi: 10.1016/j.abb.2018.04.019. Epub 2018 Apr 26.
Sulfoconjugation has been shown to be critically involved in the metabolism of acetaminophen (APAP), morphine, tapentadol and O-desmethyl tramadol (O-DMT). The objective of this study was to investigate the effects of single nucleotide polymorphisms (SNPs) of human SULT1A3 and SULT1A4 genes on the sulfating activity of SULT1A3 allozymes toward these analgesic compounds. Twelve non-synonymous coding SNPs (cSNPs) of SULT1A3/SULT1A4 were investigated, and the corresponding cDNAs were generated by site-directed mutagenesis. SULT1A3 allozymes, bacterially expressed and purified, exhibited differential sulfating activity toward each of the four analgesic compounds tested as substrates. Kinetic analyses of SULT1A3 allozymes further revealed significant differences in binding affinity and catalytic activity toward the four analgesic compounds. Collectively, the results derived from the current study showed clearly the impact of cSNPs of the coding genes, SULT1A3 and SULT1A4, on the sulfating activity of the coded SULT1A3 allozymes toward the tested analgesic compounds. These findings may have implications in the pharmacokinetics as well as the toxicity profiles of these analgesics administered in individuals with distinct SULT1A3 and/or SULT1A4 genotypes.
磺基化在对乙酰氨基酚（APAP）、吗啡、他喷他多和 O-去甲曲马多（O-DMT）的代谢中起着至关重要的作用。本研究的目的是研究人类 SULT1A3 和 SULT1A4 基因的单核苷酸多态性（SNPs）对 SULT1A3 同工酶对这些镇痛化合物的磺化活性的影响。研究了 SULT1A3/SULT1A4 的 12 个非同义编码 SNP（cSNP），并通过定点诱变生成了相应的 cDNA。细菌表达和纯化的 SULT1A3 同工酶对测试的四种镇痛化合物作为底物表现出不同的磺化活性。对 SULT1A3 同工酶的动力学分析进一步表明，它们对四种镇痛化合物的结合亲和力和催化活性存在显著差异。总的来说，当前研究的结果清楚地表明编码基因 SULT1A3 和 SULT1A4 的 cSNP 对编码的 SULT1A3 同工酶对测试的镇痛化合物的磺化活性有影响。这些发现可能对这些在具有不同 SULT1A3 和/或 SULT1A4 基因型的个体中使用的镇痛药物的药代动力学和毒性特征产生影响。
