Dissertation
ROLE OF GLUTATHIONYLATION IN THE METABOLISM OF THE ANTI-BREAST CANCER AGENT EXEMESTANE AND POTENTIAL IMPACT ON EFFICACY
Washington State University
Doctor of Philosophy (PhD), Washington State University
01/2022
DOI:
https://doi.org/10.7273/000004620
Handle:
https://hdl.handle.net/2376/118733
Abstract
Exemestane (EXE) is prescribed for the treatment of estrogen receptor positive (ER+) breast cancer as part of endocrine therapy. Clinical studies have shown that EXE as an adjuvant therapy increases disease free survival. However, response and toxicities vary significantly among patients, which may be linked to the variation in the metabolism of EXE. Previous studies indicated that cysteine conjugates of EXE and 17β-dihydro-EXE (17β-DHE) are major phase II metabolites that account for 35% and 77% of the total EXE metabolites in plasma and urine of patients, respectively. Glutathione conjugation is the first step in the formation of major cysteine conjugate metabolites. However, the glutathionylation pathway and its contribution to the inter-individual variability in the metabolism of EXE have not been previously studied. Characterization of major hepatic cytosolic glutathione-S-transferases (GSTs) revealed that GSTA1, GSTM3, and GSTM1 were active against EXE, but only GSTA1 was active against 17-DHE. Of the three isoforms, GSTA1 is the primary enzyme involved in EXE metabolism, exhibiting approximately 7.5-fold higher levels of expression in human liver than other active GSTs. The prevalent GSTA1*B allele contains a promoter region polymorphism that has been previously associated with decreased expression of the GSTA1 enzyme in vitro. Ex vivo studies utilizing liver tissues demonstrated that the GSTA1*B*B genotype is associated with a decrease in glutathione conjugation. In addition, GSTA1*B*B was associated with reductions in EXE-cys and DHE-cys in the plasma of ER+ breast cancer patients treated with EXE. These findings suggest that the GSTA1*B*B genotype is associated with interindividual variation in EXE metabolism. Additionally, in vitro aromatase inhibition studies were performed to assess the contribution of major phase II metabolites to the target anti-aromatase activity. EXE-cys demonstrated significant inhibition of the aromatase enzyme in a time dependent manner. Since aromatase is the key enzyme in the estrogen biosynthesis high circulating levels of EXE-cys in the EXE-treated patients may have a major role in lowering estrogen levels in vivo. Together, these results demonstrate that the glutathionylation pathway contributes to the variation in the EXE metabolism and may contribute to the variation in therapeutic outcomes and adverse events.
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Details
- Title
- ROLE OF GLUTATHIONYLATION IN THE METABOLISM OF THE ANTI-BREAST CANCER AGENT EXEMESTANE AND POTENTIAL IMPACT ON EFFICACY
- Creators
- Irina Leonidovna Teslenko
- Contributors
- Philip Lazarus (Advisor)Mary F. Paine (Committee Member)John D Clarke (Committee Member)Gang Chen (Committee Member)Ayesha Ahmed (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Pharmacy and Pharmaceutical Sciences, College of
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 179
- Identifiers
- 99900901438601842
- Language
- English
- Resource Type
- Dissertation