Drug metabolism reviews

Nuclear receptors and endobiotics glucuronidation: the good, the bad, and the UGT.

PMID 23330540


The recent progresses in molecular biology and pharmacology approaches allowed the characterization of a series of nuclear receptors (NRs) as efficient regulators of uridine diphosphate glucuronosyltransferase (UGT) genes activity. These regulatory processes ensure an optimized UGT expression in response to specific endo- and/or exogenous stimuli. Many of these NRs are activated by endobiotics that also are substrates for UGTs. Thus, by activating their receptors, these endogenous substances control their own conjugation, leading to the concept that glucuronidation is an important part of feed-forward/feedback mechanisms by which bioactive molecules control their own concentrations. On the other hand, numerous studies have established the pharmacological relevance of NR-UGT regulatory pathways in the response to therapeutic ligands. The present review article aims at providing a comprehensive view of the physiological and pharmacological importance of the NR regulation of the expression and activity of endobiotics-conjugating UGT enzymes. Selected examples will illustrate how the organism profits from the feed-forward/feedback mechanisms involving NR-UGT pathways, but also how such regulatory processes are involved in the initiation and/or progression of several pathological situations. Finally, we will discuss how the present pharmacopeia involves NR-dependent regulation of endobiotics glucuronidation, and whether the unexploited NR-UGT axes could serve as pharmacological targets for novel therapeutics to restore endobiotics homeostasis.