Abstract
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.
Footnotes
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↵2 Abbreviations used are: SULT, sulfotransferase; UGT, UDP-glucuronosyltransferase; COMT, catechol O-methyltransferase; S-COMT soluble catechol O-methyltransferase; MB-COMT, membrane-bound catechol O-methyltransferase; PAPS, 3′-phosphoadenosine 5′-phosphosulfate; EMBL, European Molecular Biology Laboratory; AdoMet, S-adenosyl-l-methionine; UDPGA, UDP-glucuronic acid; HPLC, high-performance liquid chromatography; PCR, polymerase chain reaction; oT, SAR, structure-activity relationship; QSAR, quantitative structure-activity relationship; HBA, hydrogen bond acceptors; PLS, partial least squares; DA, discriminant analysis.
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This work was funded by the Commission of the European Communities (Contract number BMH4-CT97–2621).
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↵1 Present address: Orion Pharma, Department of Pharmacokinetics, Espoo, Finland.
- Received April 30, 2002.
- Accepted May 15, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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