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Endocrinology Vol. 139, No. 5 2375-2381
Copyright © 1998 by The Endocrine Society

ARTICLES

Effect of Interleukins on UGT2B15 and UGT2B17 Steroid Uridine Diphosphate-Glucuronosyltransferase Expression and Activity in the LNCaP Cell Line1

Éric Lévesque2,3, Martin Beaulieu3, Chantal Guillemette3, Dean W. Hum and Alain Bélanger

Medical Research Council Group in Molecular Endocrinology, CHUL Research Center and Laval University, Québec, Canada G1V 4G2

Address all correspondence and requests for reprints to: Dr. Alain Bélanger or Dr. Dean Hum, Laboratory of Molecular Endocrinology CHUL Research Center, 2705 Laurier Boulevard, Québec, Canada G1V 4G2. E-mail: alain.belanger@crchul.ulaval.ca; or Dean.Hum{at}crchul.ulaval.ca

Cytokines are known to modulate the level of both phase 1 and phase 2 drug-metabolizing enzymes in hepatocytes. Although the effects of cytokines on cytochrome P450 (CYP450) enzymes are well understood, there is limited knowledge on how cytokines may affect steroid UDP-glucuronosyltransferase (UGT) phase 2 enzyme activity and expression in different cell types, including hepatocytes and steroid target cells. LNCaP cells, which is a human prostate cancer cell line, is a good model to study the effect of cytokines in steroid target cells because it is known to express steroidogenic enzymes, including UGT2B15 and UGT2B17, which are widely expressed steroid UGT enzymes known to conjugate androgens. In this study, we examined the possible interaction among interleukin-1{alpha} (IL-1{alpha}), IL-4, IL-6, and steroid UGT enzymes (UGT2B15 and UGT2B17). Treatment of LNCaP cells with IL-1{alpha} led to a dose-dependent inhibition of dihydrotestosterone (DHT) glucuronidation. IL-1{alpha} decreased both UGT activity and LNCaP cell proliferation in the absence and presence of DHT (0.5 nM); a maximal inhibition of 70% was observed. IL-6 inhibited LNCaP cell proliferation as well as the DHT-induced proliferation of these cells. However, neither IL-4 nor IL-6 significantly affected the formation of DHT glucuronide. Ribonuclease protection and Western blot analyses demonstrated a specific reduction of UGT2B17 transcript and protein levels in IL-1{alpha}-treated LNCaP cells. The level of UGT2B15 was not affected by cytokine treatments, indicating a differential regulation between these two UGT enzymes. Transfection experiments performed with the UGT2B17 gene promoter region indicates that the regulation occurs at the transcription level via putative cis-acting elements. This study indicates that cell proliferation and UGT expression in steroid-responsive cancer cells are differentially regulated depending on the cytokines present in the cell microenvironment.




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