Cytochrome P450 2A5 expression in a G6PD‐deficient mouse model of oxidative stress

Abstract

Murine hepatic cytochrome P450 2A5 (CYP2A5), unlike most CYP enzymes, is upregulated during hepatitis and hepatotoxicity. To determine if oxidative stress is responsible for this induction, glucose-6-phosphate dehydrogenase (G6PD)-deficient mice, that are more susceptible to oxidative stress, were treated with the prototypical CYP2A5 inducer pyrazole. Compared to normal mice, G6PD-deficient mice had 3, 1.6, and 5 times greater induction of CYP2A5 mRNA, protein, and activity, respectively. Involvement of oxidative stress was determined using markers of oxidative damage and expression of oxidant-responsive genes. Although no significant elevation in protein carbonyl groups or glutathione peroxidase and superoxide dismutase transcripts were observed, NADPH quinone oxidoreductase 1, which protects against oxidative stress and redox cycling, was increased by pyrazole. Glutathione-S-transferase (GST) alpha, mu, and pi mRNA levels were also elevated by pyrazole, with GST pi showing 1.9 times greater induction in G6PD-deficient mice. Glucose-regulated protein 78, an endoplasmic reticulum stress protein, showed a 1.7 fold greater response to pyrazole in deficient mice. These results suggest that conditions leading to upregulation of CYP2A5 are complex and factors other than oxidative stress may be involved in regulation of CYP2A5. Supported by the Natural Sciences and Engineering Research Council of Canada.