Abstract
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.
Footnotes
- Received May 10, 2014.
- Accepted August 4, 2014.
This work was supported by the National Institutes of Health [Grant DK069557].
Part of this work was presented as follows: Rohrer P and Manautou JE (2014) Let's talk about sex: is Nrf2 responsible for sex differences in susceptibility to acetaminophen-induced hepatotoxicity in mice? Poster session presented at: 53rd Society of Toxicology Annual Meeting and ToxExpo; 2014 Mar 23–27; Phoenix, AZ.
Rohrer P and Manautou JE (2013) Let's talk about sex: is Nrf2 responsible for sex differences in susceptibility to acetaminophen-induced hepatotoxicity in mice? Poster session presented at: Northeast Society of Toxicology 2013 Fall Annual Meeting, Toxicological Aspects of the Immune System; 2013 Sep 27; Cambridge, MA.
Rohrer P and Manautou JE (2013) Gender differences in mRNA and protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2-dependent genes. Poster session presented at: Gordon Research Conference, 2nd Biannual Conference on Cellular & Molecular Mechanisms of Toxicity; 2013 Aug 11–16; Andover, NH.
Rohrer P and Manautou JE (2013) Gender differences in mRNA and protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2-dependent genes. Poster session presented at: Gordon-Kenan Research Seminar, 1st Biannual Seminar on Cellular & Molecular Mechanisms of Toxicity; 2013 Aug 10–11; Andover, NH.
Rohrer P and Manautou JE (2013) Gender differences in mRNA and protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2-dependent genes. Poster session presented at: 52nd Society of Toxicology Annual Meeting and ToxExpo; 2013 Mar 10–14; San Antonio, TX.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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