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ToxSci Advance Access published online on April 11, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj192
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received December 15, 2005
Accepted April 5, 2006

Biotransformation and Toxicokinetics

Acetaminophen Metabolism Does Not Contribute to Gender Difference in Its Hepatotoxicity in Mouse

Guoli Dai 1, Lin He 1, Nathan Chou 1, and Yu-Jui Y. Wan 1 *

1 Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160

* To whom correspondence should be addressed.
Yu-Jui Y. Wan, E-mail: ywan{at}kumc.edu


  Abstract

Gender is an important factor in pharmacokinetics and pharmacodynamics. In the current study, gender difference in acetaminophen (APAP)-induced hepatotoxicity has been examined. Male and female mice were injected with a toxic dose of APAP (500 mg/kg, ip). Female mice were resistant to the hepatotoxic effects of APAP, depicted by serum alanine aminotransferase and sorbital dehydrogenase activities and histological analysis. Basal hepatic GSH levels were lower in females than in males, suggesting that basal GSH level may not be a factor in determining the gender difference of APAP hepatotoxicity. APAP metabolism was slower in females than males, revealed by lower levels of glucuronidation and sulfation and higher amounts of free APAP in the livers of female mice. Lower basal Cyp1a2 mRNA levels and lower expression of Cyp1a2 and Cyp3a11 mRNAs following APAP dosing were also observed in females compared with males. However, there was no gender difference in N-acetyl-p-benzoquinoneimine covalent binding 2 hours after APAP administration, suggesting similar APAP bioactivation between genders. Moreover, liver Gst pi mRNA levels were significantly lower in females than males. This finding is consistent with a previous report, which showed that Gst pi knockout mice are protected from APAP-induced liver toxicity. In conclusion, gender difference of APAP-induced hepatotoxicity is not likely due to APAP metabolism. Perhaps, it is in part due to gender-dependent Gst pi expression. However, the mechanism underlying the association between reduction in Gst pi expression and hepato-protective effect against APAP toxicity remains to be further explored.

Keywords: acetaminophen; gender; hepatotoxicity; cytochrome P450; glutathione S-transferase; glutathione.
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