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.

Bicalutamide (Casodex â ) is a non-steroidal pure anti-androgen used in the treatment of localized prostate cancer. It is a racemate drug, and its activity resides in the (R)-enantiomer, with little in the (S)-enantiomer. A major metabolic pathway for bicalutamide is glucuronidation catalysed by UDP-glucuronosyltransferase (UGT) enzymes. While (S)bicalutamide is directly glucuronidated, (R)bicalutamide requires hydroxylation prior to glucuronidation. The contribution of human tissues and UGT isoforms in the metabolism of these enantiomers has not been extensively investigated. In this study, both (R) and/or (S) bicalutamide were converted into glucuronide (-G) derivatives after incubation of pure and racemic solutions with microsomal extracts from human liver and kidney. Intestinal microsomes exhibited only low reactivity with these substrates. Km values of liver and kidney samples for (S)bicalutamide glucuronidation were similar, and lower than values obtained with the (R)-enantiomer. Among the 16 human UGTs tested, UGT1A8 and UGT1A9 were able to form both (S) and (R)bicalutamide-G from pure or racemic substrates. UGT2B7 was also able to form (R)bicalutamide-G. Kinetic parameters of the recombinant UGT2B7, UGT1A8 and UGT1A9 enzymes support a predominant role of the UGT1A9 isoform in bicalutamide metabolism. Accordingly, (S)bicalutamide inhibited the ability of human liver and kidney microsomes to glucuronidate the UGT1A9 probe substrate, propofol. In conclusion, the present study provides the first comprehensive analysis of in vitro bicalutamide glucuronidation by human tissues and UGTs and identifies UGT1A9 as a major contributor for (R) and (S) glucuronidation in the human liver and kidney.Bicalutamide (Casodex â , fig. 1) is a non-steroidal pure antiandrogen used for the treatment of early localized or locally advanced non-metastatic prostate cancer (reviewed in [1]). The drug is given once daily at a dosage of 150 mg as monotherapy or of 50 mg in combination with chemical or surgical castration. This pure anti-androgen competes with the active hormone, 5a-dihydrotestosterone, for androgen receptor binding and activation and thus blocks the prostate tumour growth-stimulating effects of androgens [2]. The drug used in clinic corresponds to a racemate of (R) and (S) enantiomers ( fig. 1), and its anti-androgenic activity resides almost exclusively in the (R)-enantiomer, with little, if any activity in the (S)-enantiomer [1,2]. Bicalutamide is cleared almost exclusively by metabolism. In human beings, the drug is excreted to similar extents in urine and faeces [3]. Two polar metabolites found in urines were identified as the glucuronide (-G) conjugates of (S)bicalutamide and hydroxy(R)bicalutamide [3]. Urinary concentrations of (S)bicalutamide-G are maximal 24 hr after administration of a single dose and represent up to 76% of the urinary metabolites. However, this percentage decreases to 14%, 9 days after dosage [3]. Urinary levels of the hydroxy (R)bicalutamide-G follow an inverse variation, and its...

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