Abstract 3589: Characterization of 17-dihydroexemestane glucuronidation. A role for the UGT2B17 deletion in exemestane pharmacogenetics

Abstract

Abstract Exemestane is a 3rd-generation aromatase inhibitor (AI) used in the treatment of breast cancer in postmenopausal women. Reduction to form 17-dihydroexemestane and subsequent glucuronidation to hydroexemestane-17-O-glucuronide is a major pathway for exemestane metabolism. In the present study, homogenates from a newly-developed HEK293 aromatase-overexpressing cell line (HEK293-aro) were used to examine the activity of exemestane versus 17-dihydroexemestane in vitro. 17-dihydroexemestane exhibited an inhibition of estrone formation in HEK293-aro cell homogenates (IC50=2.3±0.83 μM) that was similar to that observed for exemestane (IC50=1.4±0.42 μM). UGT-overexpressing cell lines were screened for activity against 17-dihydroexemestane and UGTs 2B17>1A10>1A8>1A4 were the only UGTs that exhibited activity. Of the hepatic UGTs, UGT2B17 exhibited a 17-fold higher Vmax/KM than UGT1A4. In human liver microsome (HLM) specimens, the rate of hydroexemestane-17-O-glucuronide formation using 17-dihydroexemestane as substrate was shown to be significantly (p<0.001) decreased (14-fold) in HLMs from subjects with the UGT2B17 (0/0) deletion genotype as compared with HLMs from subjects wild type (+/+) for UGT2B17. A significant (r2=0.72) correlation was observed between HLM hydroexemestane-17-O-glucuronide formation and liver UGT2B17 expression in the same subjects, and the KM for UGT2B17(+/+) HLMs against 17-dihydroexemestane was 7.3 μM, ∼ 2-fold lower than that observed for UGT2B17 against 17-dihydroexemestane in vitro (14.5 μM). UGT2B17 (0/0) HLMs exhibited a 1.7-fold higher KM and a 36-fold lower Vmax/KM than UGT2B17 (+/+) HLMs. These data suggest that UGT2B17 is important in the metabolism of 17-dihydroexemestane, a major active metabolite of exemestane, and that the UGT2B17 deletion could have an important role in overall patient response to exemestane. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3589.