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The Uridine Diphosphate Glucuronosyltransferase 2B15 D⁸⁵Y and 2B17 Deletion Polymorphisms Predict the Glucuronidation Pattern of Androgens and Fat Mass in Men

Center for Bone Research at the Sahlgrenska Academy (C.S., D.M., M.L., L.V., U.S., A.-L.E., C.O.), Department of Internal Medicine, Göteborg University, SE-41345 Göteborg, Sweden; Department of Laboratory Medicine (J.J., A.R.), Division of Clinical Pharmacology, Karolinska Institutet at Karolinska University Hospital, Stockholm, SE-141 86 Sweden; Clinical and Molecular Osteoporosis Research Unit (M.K.), Department of Clinical Sciences, Lund University, and Department of Orthopaedics, Malmö University Hospital, SE-20502 Malmö, Sweden; Department of Medical Sciences (O.L.), University of Uppsala, SE-751 85 Uppsala, Sweden; and Oncology and Molecular Endocrinology Research Center (A.B., F.L.), Laval University Medical Center (Centre Hospitalier de l’Université Laval) and Laval University, Quebec City, Quebec, Canada G1V 4G2

Address all correspondence and requests for reprints to: Claes Ohlsson, M.D., Ph.D., Professor, Division of Endocrinology, Department of Internal Medicine, Sahlgrenska University Hospital, SE-41345 Göteborg, Sweden. E-mail: Claes.Ohlsson{at}medic.gu.se.

Context: Previous in vitro studies have demonstrated that the UDP glucuronosyltransferase (UGT)2B15 and UGT2B17 glucuronidate androgens and their metabolites.

Objective: Our objective was to determine in vivo whether the UGT2B15 D⁸⁵Y and the UGT2B17 deletion polymorphisms predict androgen glucuronidation and body composition.

Participants: Two population-based cohorts including young adult (n = 1068; age = 18.9 yr) and elderly (n = 1001; age = 75.3 yr) men were included in the study.

Main Outcome Measures: Serum and urine levels of testosterone (T) and dihydrotestosterone (DHT) were measured by gas chromatography-mass spectrometry, and serum levels of the major glucuronidated androgen metabolites androstane-3,17β-diol(androstanediol)-3-glucuronide, androstanediol-17-glucuronide, and androsterone-glucuronide were measured by liquid chromatography-tandem mass spectrometry. Body composition was measured by dual-energy x-ray absorptiometry.

Results: Both the UGT2B15 D⁸⁵Y and the UGT2B17 deletion polymorphisms were associated with serum levels of androstanediol-17-glucuronide (P < 0.001) but not with levels of androstanediol-3-glucuronide or androsterone-glucuronide in both cohorts. Glucuronidation of T and DHT was associated with the UGT2B17 deletion but not with the UGT2B15 D⁸⁵Y polymorphism, suggested by strong associations between the deletion polymorphism and urine levels of these two hormones. Both polymorphisms were associated with several different measures of fat mass (P < 0.01). The UGT2B17 deletion polymorphism was associated with insulin sensitivity (P < 0.05) as indicated by the homeostasis model assessment index.

Conclusions: The UGT2B15 D⁸⁵Y and the UGT2B17 deletion polymorphisms are both predictors of the glucuronidation pattern of androgens/androgen metabolites. Our findings indicate that UGT2B17 is involved in 17-glucuronidation of mainly T but also of DHT and androstanediol and that UGT2B15 is involved in the 17-glucuronidation of androstanediol. Furthermore, these two polymorphisms are predictors of fat mass in men.

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