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Genetic aspects of epitestosterone formation and androgen disposition: influence of polymorphisms in CYP17 and UGT2B enzymes.

Författare och institution:
Jenny Jakobsson Schulze (-); Mattias Lorentzon (Institutionen för medicin, avdelningen för invärtesmedicin); Claes Ohlsson (Institutionen för medicin, avdelningen för invärtesmedicin); Jonas Lundmark (-); Hyung-Keun Roh (-); Anders Rane (-); Lena Ekström (-)
Publicerad i:
Pharmacogenetics and genomics, 18 ( 6 ) s. 477-85
Artikel, refereegranskad vetenskaplig
Sammanfattning (abstract):
OBJECTIVE: Testosterone is a commonly abused androgen in sports and in the gym culture of the society. Its abuse is conventionally disclosed by urinary assay of the testosterone/epitestosterone (T/E) glucuronide ratio, which should not exceed 4. A noteworthy number of athletes, however, have higher natural ratios than 4, most likely because of decreased excretion of epitestosterone glucuronide. Falsely positive doping test results are of great concern for the legal rights of the sportsman. Our objective was to study the genetic aspects of epitestosterone formation, and to elucidate the impact of genetic variation in androgen-metabolizing enzymes. METHODS: Urine from different study populations was analysed for androgen glucuronides by gas chromatography-mass spectrometry. All men were genotyped for the uridine diphospho-glucuronosyltransferase (UGT) 2B17 deletion polymorphism and single nucleotide polymorphisms in the cytochrome P-450c17alpha (CYP17), UGT2B15 and UGT2B7 genes. Expression of UGT2B15 mRNA in human liver samples was analysed using real-time PCR. RESULTS: A T>C (A1>A2) promoter polymorphism in the CYP17 gene was associated with the urinary glucuronide levels of epitestosterone and its putative precursor androstene-3beta, 17alpha-diol, resulting in 64% higher T/E ratios in A1/A1 homozygotes. Individuals devoid of UGT2B17 had significantly higher UGT2B15 mRNA levels in liver than individuals carrying two functional UGT2B17 alleles. CONCLUSION: The CYP17 promoter polymorphism may partly explain high natural (>4) T/E ratios. Our data indicate that 5-androstene-3beta, 17alpha-diol is an important precursor of epitestosterone and that CYP17 is involved in its production. In addition, we found that lack of the UGT2B17 enzyme may be compensated for by increase in UGT2B15 transcription.
Ämne (baseras på Högskoleverkets indelning av forskningsämnen):
Adolescent, Adult, Androgens, metabolism, Androstane-3,17-diol, metabolism, Base Sequence, DNA Primers, genetics, Doping in Sports, Epitestosterone, biosynthesis, urine, Gene Deletion, Gene Dosage, Glucuronosyltransferase, genetics, metabolism, Humans, Korea, Liver, metabolism, Male, Middle Aged, Pharmacogenetics, Polymorphism, Genetic, Polymorphism, Single Nucleotide, RNA, Messenger, genetics, metabolism, Steroid 17-alpha-Hydroxylase, genetics, metabolism, Testosterone, administration & dosage, metabolism, Variation (Genetics)
Postens nummer:
Posten skapad:
2008-10-09 13:12
Posten ändrad:
2010-01-26 11:04

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