RT Journal Article SR Electronic T1 Is Nuclear Factor Erythroid 2–Related Factor 2 Responsible for Sex Differences in Susceptibility to Acetaminophen-Induced Hepatotoxicity in Mice? JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1663 OP 1674 DO 10.1124/dmd.114.059006 VO 42 IS 10 A1 Philip R. Rohrer A1 Swetha Rudraiah A1 Michael J. Goedken A1 José E. Manautou YR 2014 UL http://dmd.aspetjournals.org/content/42/10/1663.abstract AB Nuclear factor erythroid 2–related factor 2 (Nrf2) is a transcription factor that positively regulates the expression and activity of cytoprotective genes during periods of oxidative stress. It has previously been shown that some Nrf2 genes are more highly expressed in livers of female than male mice. This could explain previously reported sex-related differences in susceptibility to acetaminophen (APAP) hepatotoxicity in mice, where females show greater resistance to APAP hepatotoxicity. Here, we examined, for the first time, differences in mRNA and protein expression for Nrf2 and a battery of Nrf2-dependent genes in naïve wild-type (WT) and overnight-fasted WT and Nrf2-null male and female mice following APAP treatment. Alanine aminotransferase (ALT) activity was measured as an indicator of hepatotoxicity. Hepatic mRNA and protein levels were measured by quantitative polymerase chain reaction and western blotting, respectively. Contrary to expectations, basal Nrf2 mRNA and protein expression were significantly lower in livers of naïve female than male mice. Although mRNA and/or protein expression of quinone oxidoreductase 1 and multidrug resistance–associated protein 4 was more pronounced in livers of female than male mice under some of the conditions examined, no higher global expression of Nrf2-dependent genes was detected in female mice. Furthermore, ALT activity was significantly elevated in overnight-fasted WT and Nrf2-null male mice following APAP treatment, but no increases in ALT were observed in either genotype of female mice. These results indicate that factors other than Nrf2 are responsible for the lower susceptibility of female mice to APAP hepatotoxicity.