Natural and synthetic inhibitors of UDP-glucuronosyltransferase

Glucuronidation is a major detoxification pathway in vertebrates. The react ion is catalyzed by a family of UDP-glucuronosyltransferases (UGTs) and inv olves conjugation of many endobiotic and xenobiotic substances with glucuro nic acid, forming inactive water-soluble glucuronides. UGT prevents the acc umulation of potentially toxic compounds and/or their subsequent bioactivat ion to more toxic intermediates, although biologically active glucuronides are also known. Impairment of UGTs may have important toxicological consequ ences. Substances found to inhibit or down-regulate UGT activity include en dogenous compounds, a wide range of clinically used drugs, environmental co ntaminants, and natural toxic substances present in the diet. The developme nt of selective, active-site-directed UGT inhibitors greatly enables the st udy of various UGT isoenzymes, A promising approach offers the design of tr ansition-state analogs of the glucuronidation reaction. (C) 2001 Elsevier S cience Inc. All rights reserved.