Étude de la glucuronidation des précurseurs de l'androgène actif dihydrotestostérone
|Advisor:||Guillemette, Chantal; Lévesque, Éric|
|Abstract:||Steroid hormones play a critical role in the sexual development of both men and women. The development and progression of several hormono-dependent cancers such as breast, ovarian, uterine and prostate cancers are also influenced by the bioavailability of active steroids as well as their gonadal and adrenal precursors. UDP-glucuronosyltransferase enzymes represents phase II drug-metabolizing enzymes involved in the inactivation of steroids in addition to therapeutic drugs. Variability in this pathway has the potential to affect steroids bioavailability in tissues and in blood. My work focused on the study of glucuronidation of steroid precursors (13) of dihydrotestosterone (DHT) synthesis and its metabolites. We first determined whether glucuronide (-G) derivatives of these precursors are formed in the liver, kidney and intestine. Steroid–glucuronides (-G) were demonstrated for almost every steroids tested. Of the 15 human UGT enzymes tested individually, UGT1A4 is one of the most active towards adrenal precursors (dehydroepiandrosterone, androstanediol and progestogens) and the active androgen DHT, whereas UGT1A10 is active for DHT and androstanediol. In addition, our data indicate that the variant isoforms of UGT1A4 and UGT2B7 resulting from the presence of frequent genetic polymorphisms (>5%) at codons 24 (UGT1A4*2), 48 (UGT1A4*3) and 268 (UGT2B7*2), affect enzyme activity for steroid substrates. Finally, quantification of some of these glucuronide metabolites in a small group of men and pre- and post-menopausal women supports their formation and highlight a significant inter-individual variability in their circulating levels. Additional studies are required to determine whether genetic variations in UGT genes might explain a fraction of the observed variability.|
|Document Type:||Mémoire de maîtrise|
|Open Access Date:||12 October 2018|
|Collection:||Thèses et mémoires|
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