Mammalian UDP-glucuronosyltransferase (UGT) isozymes are critical catalysts for detoxifying endogenous metabolites and numerous potentially injurious lipid-soluble phenols derived from the diet and environment. Isozymes detoxify by conjugation of glucuronic acid with metabolites, drugs, toxins, and environmental chemicals to water-soluble excretable products. Glucuornidation reactions prevent accumulation of neurotoxic levels of plasma bilirubin, as well as inactivate many drugs and avert mutagenicity and carcinogenicity of aromatic hydrocarbons--including benzo(a)pyrene-- found in cigarette smoke and automobile emissions. Moreover, UGTs prevent accumulation of dietary phenols that inhibit enzymes. On the contrary, extensive glucuronidation can also be disadvantageous. The premature clearance of many orally administered therapeutic drugs is a long-standing problem, which is associated with UGT metabolism. Metabolism is overcome by administering compensatorily higher doses that lead to serious side-effects. For decades, drug inefficiency has been the impetus to develop inhibitor(s) of UGT. The enzymatic mechanism(s) and properties that enable UGTs to convert numerous unrelated lipid-soluble phenols to innocuous glucuronides are unknown. Additionally, there are no known methods to control conjugation to prevent the premature clearance of therapeutic drugs. An important research aim, therefore, is to understand the properties and mechanism(s) that enable this system to detoxify a vast number of agents in order to maintain chemical homeostasis.
