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

G Dai, L He, N Chou, YJY Wan - Toxicological Sciences, 2006 - academic.oup.com
G Dai, L He, N Chou, YJY Wan
Toxicological Sciences, 2006academic.oup.com
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 …
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.
Oxford University Press