title: Genetic aspects of epitestosterone formation and androgen disposition: influence of polymorphisms in CYP17 and UGT2B enzymes.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet at Division of Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden. jenny.schulze@ki.se
authors.forename: Jenny Jakobsson
authors.initials: JJ
authors.lastname: Schulze
authors.forename: Mattias
authors.initials: M
authors.lastname: Lorentzon
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
authors.forename: Jonas
authors.initials: J
authors.lastname: Lundmark
authors.forename: Hyung-Keun
authors.initials: HK
authors.lastname: Roh
authors.forename: Anders
authors.initials: A
authors.lastname: Rane
authors.forename: Lena
authors.initials: L
authors.lastname: Ekström
mesh_terms: D000293:Adolescent; D000328:Adult; D000728:Androgens / Q000378:metabolism*; D015113:Androstane-3,17-diol / Q000378:metabolism; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004300:Doping in Sports; D004845:Epitestosterone / Q000096:biosynthesis* / Q000652:urine; D017353:Gene Deletion; D018628:Gene Dosage; D014644:Genetic Variation; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007723:Korea; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D013739:Testosterone / Q000008:administration & dosage / Q000378:metabolism
chemical_list: D000728:Androgens; D017931:DNA Primers; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; D015113:Androstane-3,17-diol; D013739:Testosterone; D004845:Epitestosterone; D013254:Steroid 17-alpha-Hydroxylase; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; C472000:UDP-glucuronosyltransferase 2B15, human; C500513:UGT2B17 protein, human