Doping and Genetic Testing: Sex Difference in UGT2B15 Expression, Testosterone Glucuronidation Activity and Urinary Testosterone/ Epitestosterone Glucuronide Ratio

Lena      Ekstrom; Erdal      Gok; Maria      Johansson; Mats      Garle; Anders      Rane; Jenny      J. Schulze

doi:10.2174/187569212800626403

Abstract

Doping with testosterone is conventionally detected by urinary assay of the testosterone/epitestosterone (T/E) glucuronide ratio. This ratio is strongly associated with a deletion polymorphism in the UDP-glucuronosyltransferase (UGT) 2B17 gene. The metabolism of certain UGT specific drugs has been shown to be different in men and women. The objective of this study was to evaluate the impact of gender as well as human genetic variation on testosterone metabolism and the T/E ratio. We also carried out legal and policy analysis of the extant regulatory documents with a view to assess their preparedness for the introduction of genetic testing to the field of doping, and interpretation of doping related tests in the future. Testosterone glucuronidation rate was measured in female and male liver microsomes and analyzed with HPLC. UGT2B15 mRNA was measured in human liver samples using real-time PCR. Elite athletes participating in different endurance sports were genotyped for the UGT2B17 deletion polymorphism and compared with their urinary T/E ratio. The testosterone glucuronidation rate was 1.7 times higher in male than in female liver microsomes (p <0.05). Male del/del livers had significantly higher expression of UGT2B15 compared to female del/del livers (p <0.05). Men, but not women, seem to compensate for their lack of UGT2B17 activity with increased UGT2B15 expression. The T/E ratios in males, but not in females, are strongly associated with the UGT2B17 ins/ins and ins/del genotype (p <0.05).The results presented herein directly inform the ways in which doping tests may have to be designed and interpreted in the future so as to take into account host (athletes’) individual characteristics and gene-by-gender interactions. Additionally we suggest that the current legal and policy frameworks are in need of substantive amendment if the field of doping testing is to benefit from advances in genomics technologies and personalized medicine.

Keywords: Androgens, doping and genetic testing convergence, sex difference, legal and technology policy analysis, sports medicine, T/E ratio, testosterone, UGT2B17