Acetaminophen metabolism does not contribute to gender difference in its hepatotoxicity in mouse

Guoli Dai, Lin He, Nathan Chou, Yu-Jui Yvonne Wan

Research output: Contribution to journalArticle

65 Scopus citations

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 reduced glutathione (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 after APAP dosing were also observed in females compared with males. However, there was no gender difference in N-acetyl-p-benzoquinone imine covalent binding 2 h 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 hepatoprotective effect against APAP toxicity remains to be further explored.

Original languageEnglish (US)
Pages (from-to)33-41
Number of pages9
JournalToxicological Sciences
Volume92
Issue number1
DOIs
StatePublished - Jul 2006
Externally publishedYes

Keywords

  • Acetaminophen
  • Cytochrome P450
  • Gender
  • Glutathione
  • Glutathione S-transferase
  • Hepatotoxicity

ASJC Scopus subject areas

  • Toxicology

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