4-Aminobiphenyl (ABP) is a trace component of cigarette
smoke and
hair dyes, a suspected human
carcinogen and a potent rodent liver
carcinogen. Postnatal exposure of mice to ABP results in a higher incidence of liver
tumors in males than in females, paralleling the sex difference in human
liver cancer incidence. A traditional model of ABP
tumorigenesis involves initial CYP1A2-mediated N-hydroxylation, which eventually leads to production of mutagenic ABP-
DNA adducts that initiate
tumor growth. However, several studies have found no correlation between sex or
CYP1A2 function and the
DNA-damaging, mutagenic, or tumorigenic effects of ABP. Oxidative stress may be an important etiological factor for
liver cancer, and it has also been linked to ABP exposure. The goals of this study were to identify novel
enzyme(s) that contribute to ABP N-oxidation, and to investigate a potential role for oxidative stress in ABP liver tumorigenicity.
Isozyme-selective inhibition experiments using liver microsomes from wild-type and genetically modified mice identified
CYP2E1 as a major ABP N-hydroxylating
enzyme. The N-hydroxylation of ABP by transiently expressed
CYP2E1 produced oxidative stress in cultured mouse
hepatoma cells. In vivo postnatal exposure of mice to a tumorigenic dose of ABP also produced oxidative stress in male wild-type mice, but not in male
Cyp2e1(-/-) mice or in female mice. However, a stronger NRF2-associated
antioxidant response was observed in females. Our results identify
CYP2E1 as a novel ABP-N-oxidizing
enzyme, and suggest that sex differences in CYP2E1-dependent oxidative stress and
antioxidant responses to ABP may contribute to the observed sex difference in
tumor incidence.