TITLE

Molecular mechanism of 17α-ethinylestradiol cytotoxicity in isolated rat hepatocytes

AUTHOR(S)
Wan, Luke; O'Brien, Peter
PUB. DATE
January 2014
SOURCE
Canadian Journal of Physiology & Pharmacology;Jan2014, Vol. 92 Issue 1, p21
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
17α-Ethinylestradiol (17-EE) is used in formulations of contraceptives and hormone replacement therapy because it is an estradiol derivative. However, it has been associated with an increase in the risk of liver cancers and injury. The carcinogenic properties of 17-EE are similar to that of other estrogens, but the molecular mechanism of liver injury is still unclear. It is important to identify any secondary toxic mechanisms that can be used to prevent or treat the toxicity. The LC50 of 17-EE toward isolated rat hepatocytes was determined to be 150 ± 8 μmol/L. Accelerated cytotoxicity mechanism screening (ACMS) techniques using isolated rat hepatocytes showed that CYP1A inhibitors decreased cytotoxicity, whereas tyrosinase increased toxicity; this suggests that the toxic mechanism involved is the oxidation of 17-EE. A hepatocyte inflammation model also increased 17-EE-induced mitochondrial toxicity, as well as the formation of ROS and H2O2. Cytotoxicity was increased when inhibitors of quinone reduction, catechol- O-methylation, glucuronidation, glutathione conjugation, and sulfation were co-incubated with 17-EE. The hepatocytes could be rescued with antioxidants and quinone trapping agents, thereby suggesting a role for quinoid moiety induced oxidative stress in 17-EE induced cytotoxicity. These mechanisms for 17-EE hepatotoxicity could provide a new perspective for the treating 17-EE-induced liver injury.
ACCESSION #
93433858

 

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