Taskinen Jyrki, Ethell Brian T, Pihlavisto Pia, Hood Alan M, Burchell Brian, Coughtrie Michael W H
Department of Pharmacy, University of Helsinki, Helsinki, Finland.
Drug Metab Dispos. 2003 Sep;31(9):1187-97. doi: 10.1124/dmd.31.9.1187.
Conjugation of a structurally diverse set of 53 catechol compounds was studied in vitro using six recombinant human sulfotransferases (SULTs), five UDP-glucuronosyltransferases (UGT) and the soluble form of catechol O-methyltransferase (S-COMT) as catalyst. The catechol set comprised endogenous compounds, such as catecholamines and catecholestrogens, drugs, natural plant constituents, and other catechols with diverse substituent properties and substitution patterns. Most of the catechols studied were substrates of S-COMT and four SULT isoforms (1A1, 1A2, 1A3, and 1B1), but the rates of conjugation varied considerably, depending on the substrate structure and the enzyme form. SULT1E1 sulfated fewer catechols. Only low activities were observed for SULT1C2. UGT1A9 glucuronidated catechols representing various structural classes, and almost half of the studied compounds were glucuronidated at a high rate. The other UGT enzymes (1A1, 1A6, 2B7, and 2B15) showed narrower substrate specificity for catechols, but each glucuronidated some catechols at a high rate. Dependence of specificity and rate of conjugation on the molecular structure of the substrate was characterized by structure-activity relationship analysis and quantitative structure-activity relationship modeling. Twelve structural descriptors were used to characterize lipophilicity/polar interaction properties, steric properties, and electronic effects of the substituents modifying the catechol structure. PLS models explaining more than 80% and predicting more than 70% of the variance in conjugation activity were derived for the representative enzyme forms SULT1A3, UGT1A9, and S-COMT. Several structural factors governing the conjugation of catechol hormones, metabolites, and drugs were identified. The results have significant implications for predicting the metabolic fate of catechols.
使用六种重组人磺基转移酶（SULTs）、五种尿苷二磷酸葡萄糖醛酸基转移酶（UGT）和儿茶酚-O-甲基转移酶的可溶性形式（S-COMT）作为催化剂，在体外研究了53种结构多样的儿茶酚化合物的结合反应。儿茶酚组包括内源性化合物，如儿茶酚胺和儿茶酚雌激素、药物、天然植物成分以及其他具有不同取代基性质和取代模式的儿茶酚。所研究的大多数儿茶酚是S-COMT和四种SULT同工型（1A1、1A2、1A3和1B1）的底物，但结合反应速率差异很大，这取决于底物结构和酶的形式。SULT1E1使较少的儿茶酚硫酸化。仅观察到SULT1C2的活性较低。UGT1A9使代表各种结构类别的儿茶酚葡萄糖醛酸化，并且几乎一半的研究化合物以高速率葡萄糖醛酸化。其他UGT酶（1A1、1A6、2B7和2B15）对儿茶酚的底物特异性较窄，但每种酶都使一些儿茶酚以高速率葡萄糖醛酸化。通过结构-活性关系分析和定量结构-活性关系建模，表征了结合特异性和速率对底物分子结构的依赖性。使用12种结构描述符来表征修饰儿茶酚结构的取代基的亲脂性/极性相互作用性质、空间性质和电子效应。针对代表性酶形式SULT1A3、UGT1A9和S-COMT，推导了解释超过80%并预测结合活性中超过70%方差的PLS模型。确定了几个控制儿茶酚激素、代谢物和药物结合的结构因素。这些结果对预测儿茶酚的代谢命运具有重要意义。
