Burchell B, Coughtrie M W
Department of Biochemical Medicine, Ninewells Medical School, University, Dundee, Scotland, UK.
Environ Health Perspect. 1997 Jun;105 Suppl 4(Suppl 4):739-47. doi: 10.1289/ehp.97105s4739.
Glucuronidation and sulfation are phase 2 metabolic reactions catalyzed by large families of different isoenzymes in man. The textbook view that glucuronidation and sulfation lead to the production of harmless conjugates for simple excretion is not valid. Biologically active and toxic sulfates and glucuronides are produced and leed to adverse drug reactions, including immune hypersensitivity. Considerable variation in xenobiotic conjugation is observed as a result of altered expression of UDP-glucuronosyltransferases (UGTs) and sulfotransferases (STs). Recent cloning and expression of human cDNA encoding UGTs and STs has facilitated characterization of isoform substrate specificity, which has been further validated using specific antibodies and human tissue fractions. The availability of cloned/expressed human enzymes and specific antibodies has enabled the investigation of xenobiotic induction and metabolic disruption leeding to adverse responses. Genetic polymorphisms of glucuronidation and sulfation are known to exist although the characterization and assessment of the importance of these variations are hampered by appropriate ethical studies in men with suitable safe model compounds. Genetic analysis has allowed molecular identification of defects in well-known hyperbilirubinemias. However, full characterization of the specific functional roles of human UGTs and STs requires rigorous kinetic and molecular analyses of the role of each enzyme in vivo through the use of specific antibodies and inhibitors. This will leed to the better prediction of variation of xenobiotic glucuronidation and sulfation in man.
葡萄糖醛酸化和硫酸化是人体中由大量不同同工酶家族催化的Ⅱ相代谢反应。认为葡萄糖醛酸化和硫酸化会产生无害结合物以便简单排泄的传统观点并不正确。生物活性和有毒的硫酸盐及葡萄糖醛酸化物会产生，并导致药物不良反应，包括免疫超敏反应。由于尿苷二磷酸葡萄糖醛酸基转移酶（UGTs）和磺基转移酶（STs）表达的改变，观察到外源性物质结合存在相当大的差异。最近对编码UGTs和STs的人类cDNA的克隆和表达有助于表征同工型底物特异性，使用特异性抗体和人体组织部分已进一步验证了这一点。克隆/表达的人类酶和特异性抗体的可获得性使得对外源性物质诱导和导致不良反应的代谢紊乱的研究成为可能。已知存在葡萄糖醛酸化和硫酸化的基因多态性，尽管对这些变异重要性的表征和评估因使用合适的安全模型化合物对人体进行适当的伦理研究而受到阻碍。基因分析已使人们能够从分子水平鉴定出已知的高胆红素血症中的缺陷。然而，要全面表征人类UGTs和STs的特定功能作用，需要通过使用特异性抗体和抑制剂对每种酶在体内的作用进行严格的动力学和分子分析。这将有助于更好地预测人体中外源性物质葡萄糖醛酸化和硫酸化的变异情况。
