Genetic Variation in SLCO2B1 is Associated with Serum Levels of Testosterone and its Metabolites Prior to and Two Days after Testosterone Administration

Jenny      Schulze; Maria      Johansson; Anders      Rane; Lena      Ekstrom

doi:10.2174/187569212802510021

Abstract

Organic anion transporting polypeptides (OATP/SLCO) 2B1 and 1B3 mediate the cellular influx of androgens. Very few studies have specifically evaluated genetic variation and androgen transport. The aim of this study was to evaluate if human genetic variation in SLCO2B1 and SLCO1B3 genes are associated with the disposition of testosterone and five of its metabolites before and two days after the administration of a single intramuscular dose (500 mg) of testosterone enanthate in healthy volunteers (N=43). Serum concentration of testosterone and its metabolites were determined by GCMS/LCMS. Two functional polymorphisms in SLCO2B1 (rs12422149) and SLCO1B3 (rs4149117) genes were characterized by allelic discrimination. These SNPs have been hitherto shown to markedly affect the cellular uptake of hormones and hence, they were selected. Individuals homozygous for the SLCO2B1 G-allele displayed lower levels of total testosterone prior to (5.09 ng/ml) and two days after (13.58 ng/ml) testosterone injection, as compared to individuals expressing the A-allele (6.01 ng/ml and 21.88 ng/ml, respectively) (p=0.05 and p=0.002, respectively). Moreover, the concentration of the testosterone metabolites (dihydrotestosterone (DHT), androsterone, 5α-androstane- 3α,17β-diol-17-glucuronide) were significantly lower in subjects with GG genotype at 48 hours post-dose. Individuals homozygous for the SLCO2B1 G allele had a smaller increase in serum testosterone and DHT levels (0.03-fold/kg and 0.02-fold/kg) compared to carriers of the A allele (0.05-fold/kg and 0.03-fold/kg) (p=0.04 and p=0.02, respectively). The SLCO1B3 polymorphism did not show any significant association with serum testosterone levels or the other androgens metabolites investigated. In conclusion, here we report, for the first time to the best of our knowledge, that genetic variation in SLCO2B1 gene impacts the systemic concentrations of testosterone and some of its metabolites, after administration of a single-dose testosterone enanthate. These data also serve as a foundation to examine in the future the role of human genetic variation in SLCO2B1 in relation to testosterone pharmacokinetics, particularly in the context of sports medicine and doping testing or clinical use as a replacement therapy.

Keywords: Diagnostics for sports medicine, Doping and genetic testing, genetic variation, personalized medicine, SLCO2B1, testosterone.

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