Department of Pharmacology (S.D.) and Institute of Environmental Health Sciences (J.A.C., T.A.K., M.R.-M.), Wayne State University, Detroit, Michigan; Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, Missouri (R.G., C.A.V.); Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina (P.C.S.); and Office of Research and Development, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina (R.N.H.).
Department of Pharmacology (S.D.) and Institute of Environmental Health Sciences (J.A.C., T.A.K., M.R.-M.), Wayne State University, Detroit, Michigan; Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, Missouri (R.G., C.A.V.); Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina (P.C.S.); and Office of Research and Development, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina (R.N.H.)
Drug Metab Dispos. 2019 Jun;47(6):592-600. doi: 10.1124/dmd.119.086363. Epub 2019 Mar 18.
The liver is the predominant organ of metabolism for many endogenous and foreign chemicals. Cytosolic sulfotransferases (SULTs) catalyze the sulfonation of drugs and other xenobiotics, as well as hormones, neurotransmitters, and sterols, with consequences that include enhanced drug elimination, hormone inactivation, and procarcinogen bioactivation. SULTs are classified into six gene families, but only SULT1 and SULT2 enzymes are expressed in human liver. We characterized the developmental expression patterns of SULT1 and SULT2 mRNAs and proteins in human liver samples using reverse transcription quantitative polymerase chain reaction (RT-qPCR), RNA sequencing, and targeted quantitative proteomics. Using a set of prenatal, infant, and adult liver specimens, RT-qPCR analysis demonstrated that () expression did not vary appreciably during development; , , and mRNA levels were highest in prenatal and/or infant liver, and , , and mRNA levels were highest in infant and/or adult. Hepatic (), , and mRNA levels were low regardless of developmental stage. Results obtained with RNA sequencing of a different set of liver specimens (prenatal and pediatric) were generally comparable results to those of the RT-qPCR analysis, with the additional finding that expression was highest during gestation. Analysis of SULT protein content in a library of human liver cytosols demonstrated that protein levels generally corresponded to the mRNAs, with the major exception that SULT1C4 protein levels were much lower than expected based on mRNA levels. These findings further support the concept that hepatic SULTs play important metabolic roles throughout the human life course, including early development.
肝脏是许多内源性和外源性化学物质代谢的主要器官。细胞溶质磺基转移酶(SULTs)催化药物和其他外源性化学物质以及激素、神经递质和甾体的磺化,其后果包括增强药物消除、激素失活和前致癌物的生物激活。SULTs 分为六个基因家族,但只有 SULT1 和 SULT2 酶在人肝中表达。我们使用逆转录定量聚合酶链反应(RT-qPCR)、RNA 测序和靶向定量蛋白质组学,研究了 SULT1 和 SULT2 mRNA 和蛋白质在人肝组织中的发育表达模式。使用一组产前、婴儿和成人肝标本,RT-qPCR 分析表明,()表达在发育过程中没有明显变化;、、和 mRNA 水平在产前和/或婴儿肝中最高,、、和 mRNA 水平在婴儿和/或成人肝中最高。肝()、、和 mRNA 水平无论发育阶段如何均较低。用另一组肝标本(产前和儿科)进行 RNA 测序获得的结果与 RT-qPCR 分析的结果基本一致,另外还发现表达在妊娠期间最高。人肝胞质体 SULT 蛋白含量分析表明,蛋白水平通常与 mRNA 相对应,主要例外是 SULT1C4 蛋白水平远低于基于 mRNA 水平的预期。这些发现进一步支持了这样一种概念,即肝 SULTs 在人类整个生命周期中都发挥着重要的代谢作用,包括早期发育。