ArticlePharmacogenetics and genomics2010
Characterization of 17-dihydroexemestane glucuronidation: potential role of the UGT2B17 deletion in exemestane pharmacogenetics.
Article in Pharmacogenetics and genomics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 61 citations in OpenAlex.
- Prognostic impact of genetic variants of CYP19A1 and UGT2B17 in a randomized trial for endocrine-responsive postmenopausal breast cancer.The pharmacogenomics journal · 2020Trial
- Roles of Uridine Diphosphoglucuronosyltransferase 2B Enzymes in Cancer Susceptibility and Treatment: A Review.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Impact of combined UGT2B17 and GSTA1 genotypes on exemestane pharmacogenetics.Drug metabolism and disposition: the biological fate of chemicals · 2025Article
- Determination and Disposition of the Aromatase Inhibitor Exemestane in CYP3A-Deficient Mice.Molecules (Basel, Switzerland) · 2025Article
- Intestinal Metabolism of Diclofenac by Polymorphic UGT2B17 Correlates with its Highly Variable Pharmacokinetics and Safety across Populations.Clinical pharmacology and therapeutics · 2023Article
- Article
- Influence of Glutathione-S-Transferase A1*B Allele on the Metabolism of the Aromatase Inhibitor, Exemestane, in Human Liver Cytosols and in Patients Treated With Exemestane.The Journal of pharmacology and experimental therapeutics · 2022Article
- Article
- Simultaneous Quantification of Aromatase Inhibitors and Estrogens in Postmenopausal Breast Cancer Patients.The Journal of clinical endocrinology and metabolism · 2022Article
- Characterization of Cytosolic GlutathioneDrug metabolism and disposition: the biological fate of chemicals · 2021Article
- Variation in the UGT2B17 genotype, exemestane metabolism and menopause-related toxicities in the CCTG MAP.3 trial.Breast cancer research and treatment · 2020Article
- Genetic Underpinnings of Musculoskeletal Pain During Treatment With Aromatase Inhibitors for Breast Cancer: A Biological Pathway Analysis.Biological research for nursing · 2020Article
- Factors Affecting Interindividual Variability of Hepatic UGT2B17 Protein Expression Examined Using a Novel Specific Monoclonal Antibody.Drug metabolism and disposition: the biological fate of chemicals · 2019Article
- Identification and Quantification of Novel Major Metabolites of the Steroidal Aromatase Inhibitor, Exemestane.Drug metabolism and disposition: the biological fate of chemicals · 2018Article
- Hepatic Abundance and Activity of Androgen- and Drug-Metabolizing Enzyme UGT2B17 Are Associated with Genotype, Age, and Sex.Drug metabolism and disposition: the biological fate of chemicals · 2018Article
- Role of the UGT2B17 deletion in exemestane pharmacogenetics.The pharmacogenomics journal · 2018Article
- Regulation of Hepatic UGT2B15 by Methylation in Adults of Asian Descent.Pharmaceutics · 2018Article
- Polymorphisms in drug-metabolizing enzymes and steady-state exemestane concentration in postmenopausal patients with breast cancer.The pharmacogenomics journal · 2017Article
- Impact of the OATP1B1 c.521T>C single nucleotide polymorphism on the pharmacokinetics of exemestane in healthy post-menopausal female volunteers.Journal of clinical pharmacy and therapeutics · 2017Article
- In vitro metabolism of exemestane by hepatic cytochrome P450s: impact of nonsynonymous polymorphisms on formation of the active metabolite 17Pharmacology research & perspectives · 2017Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
objectiveExemestane 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.
methodsHomogenates 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.
resultsThe 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.
conclusionThese 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.
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