Characterization of 17-dihydroexemestane glucuronidation: potential role of the UGT2B17 deletion in exemestane pharmacogenetics

Pharmacogenet Genomics. 2010 Oct;20(10):575-85. doi: 10.1097/FPC.0b013e32833b04af.


Objective: Exemestane is a third-generation aromatase inhibitor used in the treatment of breast cancer in postmenopausal women. Reduction to form 17-dihydroexemestane and subsequent glucuronidation to exemestane-17-O-glucuronide is a major pathway for exemestane metabolism. The goal of this study was to analyze 17-dihydroexemestane anti-aromatase activity, characterize the 17-dihydroexemestane glucuronidation pathway, and determine whether the functional polymorphisms in active UGTs could play a role in altered 17-dihydroexemestane glucuronidation.

Methods: Homogenates from a HEK293 aromatase-overexpressing cell line (HEK293-aro) were used to examine exemestane versus 17-dihydroexemestane anti-aromatase activities. UGT-overexpressing cell lines and a panel (n=110) of human liver microsome (HLM) were screened for glucuronidation activity against 17-dihydroexemestane. UGT2B17 genotyping and liver mRNA expression were performed by real-time PCR.

Results: The inhibition of estrone formation from androst-4-ene-3,17-dione in HEK293-aro cell homogenates was similar for 17-dihydroexemestane (IC(50)=2.3±0.83 μmol/l) and exemestane (IC(50)=1.4±0.42 μmol/l). UGTs 2B17 and 1A4 were high-expression hepatic UGTs that exhibited activity against 17-dihydroexemestane, with UGT2B17 exhibiting a 17-fold higher V(max)/K(M) than UGT1A4. The rate of exemestane-17-O-glucuronide formation was shown to be significantly (P<0.001) decreased (14-fold) in HLMs exhibiting the UGT2B17(*2/*2) deletion genotype versus wild-type UGT2B17(*1/*1) HLMs; a 36-fold lower V(max)/K(M) (P=0.023) was observed in UGT2B17(*2/*2) versus UGT2B17(*1/*1) HLMs. A significant (P<0.0001, R(2)=0.72) correlation was observed between HLM exemestane-17-O-glucuronide formation and liver UGT2B17 expression.

Conclusion: These data suggest that 17-dihydroexemestane is an active metabolite of exemestane and that the UGT2B17 deletion polymorphism could play an important role in determining levels of excretion of 17-dihydroexemestane and overall exemestane metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Androstadienes / chemistry
  • Androstadienes / metabolism*
  • Androstadienes / pharmacology*
  • Aromatase / metabolism
  • Aromatase Inhibitors / chemistry
  • Aromatase Inhibitors / metabolism
  • Aromatase Inhibitors / pharmacology
  • Cell Line
  • Chromatography, High Pressure Liquid
  • Gene Deletion*
  • Glucuronides / metabolism*
  • Glucuronosyltransferase / genetics*
  • Glycosylation / drug effects
  • Humans
  • Kinetics
  • Liver / drug effects
  • Liver / enzymology
  • Mass Spectrometry
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Minor Histocompatibility Antigens


  • Androstadienes
  • Aromatase Inhibitors
  • Glucuronides
  • Minor Histocompatibility Antigens
  • Aromatase
  • Glucuronosyltransferase
  • UGT2B17 protein, human
  • 17-dihydroexemestane