ArticlePharmacogenetics and genomics2016
Impact of nonsynonymous single nucleotide polymorphisms on in-vitro metabolism of exemestane by hepatic cytosolic reductases.
Article in Pharmacogenetics and genomics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 31 citations in OpenAlex.
- Impact of combined UGT2B17 and GSTA1 genotypes on exemestane pharmacogenetics.Drug metabolism and disposition: the biological fate of chemicals · 2025Article
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- Pharmacogenetics and Oxcarbazepine in Children and Adolescents: BeyondJournal of child and adolescent psychopharmacology · 2024Review
- Germline Mutations in Steroid Metabolizing Enzymes: A Focus on Steroid Transforming Aldo-Keto Reductases.International journal of molecular sciences · 2023Review
- 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
- Characterization of the major single nucleotide polymorphic variants of aldo-keto reductase 1C3 (type 5 17β-hydroxysteroid dehydrogenase).The Journal of steroid biochemistry and molecular biology · 2022Article
- Characterization of Cytosolic GlutathioneDrug metabolism and disposition: the biological fate of chemicals · 2021Article
- Aldo-Keto Reductases and Cancer Drug Resistance.Pharmacological reviews · 2021Review
- Intracrinology-revisited and prostate cancer.The Journal of steroid biochemistry and molecular biology · 2020Review
- Intracrine androgen biosynthesis and drug resistance.Cancer drug resistance (Alhambra, Calif.) · 2020Review
- In vitro Transport Ability ofOncoTargets and therapy · 2020Article
- AKR1C3 (type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase): Roles in malignancy and endocrine disorders.Molecular and cellular endocrinology · 2019Review
- Structural and Functional Biology of Aldo-Keto Reductase Steroid-Transforming Enzymes.Endocrine reviews · 2019Review
- Identification and Quantification of Novel Major Metabolites of the Steroidal Aromatase Inhibitor, Exemestane.Drug metabolism and disposition: the biological fate of chemicals · 2018Article
- Carbonyl reduction of NNK by recombinant human lung enzymes: identification of HSD17β12 as the reductase important in (R)-NNAL formation in human lung.Carcinogenesis · 2018Article
- Role of the UGT2B17 deletion in exemestane pharmacogenetics.The pharmacogenomics journal · 2018Article
- In vitro metabolism of exemestane by hepatic cytochrome P450s: impact of nonsynonymous polymorphisms on formation of the active metabolite 17Pharmacology research & perspectives · 2017Article
- Exemestane potency is unchanged by common nonsynonymous polymorphisms in CYP19A1: results of a novel anti-aromatase activity assay examining exemestane and its derivatives.Pharmacology research & perspectives · 2017Article
- Germline genetic predictors of aromatase inhibitor concentrations, estrogen suppression and drug efficacy and toxicity in breast cancer patients.Pharmacogenomics · 2017Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
objectiveExemestane (EXE) is a potent third-generation aromatase inhibitor used as endocrine therapy in breast cancer treatment and prevention. Characterization of its metabolic pathway is incomplete, with ambiguity existing in the identity of enzymes driving the production of its key metabolite, 17β-dihydroexemestane (17β-DHE). The impact of genetic variation on EXE metabolism is also unknown. This study aims to describe cytosolic reductase involvement in hepatic EXE metabolism and to assess the impact of functional polymorphisms on metabolite production. MATERIALS AND
methodsPhase I metabolites were identified in incubations of EXE with pooled human liver cytosol or recombinant protein for AKR1Cs and CBR1. Kinetic parameters characterizing EXE reduction were measured for purified wild-type enzymes, and nonsynonymous variants occurring at greater than 1% minor allele frequency using UPLC/MS/MS.
resultsHuman liver cytosol, CBR1, AKR1C1, AKR1C2, AKR1C3, and AKR1C4 reduce EXE to active primary metabolite 17β-DHE. The formation of a novel metabolite, 17α-DHE, was catalyzed by recombinant AKR1C4 and CBR1 in addition to hepatic cytosol. Variants AKR1C3 Arg258Cys and AKR1C4 Gly135Glu had significantly decreased affinity for EXE relative to their respective wild types. Five common AKR1C3 polymorphisms were associated with decreased rates of catalysis, whereas AKR1C4 Gly135Glu increased the velocity of EXE reduction.
conclusionAKR1Cs and CBR1 catalyze EXE reduction in vitro. These results imply that cytosolic ketosteroid reductases may participate in the EXE metabolic pathway in vivo. In addition, several common variants were associated with altered enzymatic activity, suggesting that functional polymorphisms could play an important role in overall EXE metabolism and activity by altering the extent and duration of 17β-DHE exposure.
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