Severity: Warning
Message: fopen(/var/lib/php/sessions/ci_sessionogaep0iavo3bkqt11uf2ulp7859vb5td): Failed to open stream: No space left on device
Filename: drivers/Session_files_driver.php
Line Number: 177
Backtrace:
File: /var/www/html/index.php
Line: 316
Function: require_once
Severity: Warning
Message: session_start(): Failed to read session data: user (path: /var/lib/php/sessions)
Filename: Session/Session.php
Line Number: 137
Backtrace:
File: /var/www/html/index.php
Line: 316
Function: require_once
Severity: Warning
Message: file_get_contents(https://...@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
Filename: helpers/my_audit_helper.php
Line Number: 143
Backtrace:
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 143
Function: file_get_contents
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 209
Function: simplexml_load_file_from_url
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 994
Function: getPubMedXML
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 3134
Function: GetPubMedArticleOutput_2016
File: /var/www/html/application/controllers/Detail.php
Line: 574
Function: pubMedSearch_Global
File: /var/www/html/application/controllers/Detail.php
Line: 488
Function: pubMedGetRelatedKeyword
File: /var/www/html/index.php
Line: 316
Function: require_once
Exemestane (EXE) is used to treat postmenopausal women diagnosed with estrogen receptor positive (ER+) breast cancer. A major mode of metabolism of EXE and its active metabolite, 17-dihydroexemestane, is via glutathionylation by glutathione-S-transferase (GST) enzymes. The goal of the present study was to investigate the effects of genetic variation in EXE-metabolizing GST enzymes on overall EXE metabolism. Ex vivo assays examining human liver cytosols from 75 subjects revealed the genotype was associated with significant decreases in S-(androsta-1,4-diene-3,17-dion-6-ylmethyl)-L-glutathione ( = 0.034) and S-(androsta-1,4-diene-17-ol-3-on-6-ylmethyl)-L-gutathione ( = 0.014) formation. In the plasma of 68 ER+ breast cancer patients treated with EXE, the genotype was associated with significant decreases in both EXE-cysteine (cys) (29%, = 0.0056) and 17-DHE-cys (34%, = 0.032) as compared with patients with the genotype, with significant decreases in EXE-cys ( = 0.0067) and 17-DHE-cys ( = 0.028) observed in patients with increasing numbers of the allele. A near-significant ( = 0.060) trend was also observed for urinary EXE-cys levels from the same patients. In contrast, plasma and urinary 17-DHE-Gluc levels were significantly increased (36%, = 0.00097 and 52%, = 0.0089; respectively) in patients with the genotype. No significant correlations were observed between the GSTM1 null genotype and EXE metabolite levels. These data suggest that the allele is associated with interindividual differences in EXE metabolism and may play a role in interindividual variability in overall response to EXE. SIGNIFICANCE STATEMENT: The present study is the first comprehensive pharmacogenomic investigation examining the role of genetic variability in GST enzymes on exemestane metabolism. The GSTA1 *B*B genotype was found to contribute to interindividual differences in the metabolism of EXE both ex vivo and in clinical samples from patients taking EXE for the treatment of ER+ breast cancer. Since GSTA1 is a major hepatic phase II metabolizing enzyme in EXE metabolism, the GSTA1*B allele may be an important biomarker for treatment outcomes and toxicities.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9426760 | PMC |
http://dx.doi.org/10.1124/jpet.122.001232 | DOI Listing |
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!