| 4-Aminobiphenyl (ABP) is a human carcinogen commonly found in cigarette smoke and hair dyes. In a tumor study carried out previously in our laboratory using ABP, female mice showed a dramatically lower incidence of liver tumors than male mice. This observation seems to parallel the prominent sex difference observed in human liver cancer, with women having a 3- to 5-fold lower incidence than men. Our overall goal is to elucidate the molecular mechanisms behind ABP-induced liver carcinogenesis in our mouse model, which we hope will improve our understanding of ABP as an important environmental carcinogen and also shed light on the molecular mechanism behind human liver cancer. According to a traditional model of ABP carcinogenesis, ABP N-hydroxylation by CYP1A2 initiates a cascade of bioactivation reactions that ultimately result in the formation of ABP-DNA adducts and the initiation of liver carcinogenesis. In the first part of my PhD studies, I generated evidence against this traditional model of ABP carcinogenesis by finding no sex differences in ABP-induced mutations in mouse liver. Re-examination of the ABP bioactivation pathway using both genetic and pharmacological tools revealed CYP2E1 as a novel major ABP N-hydroxylation enzyme in mouse liver. No sex differences were found in ABP N-hydroxylation activity. Since oxidative stress has been linked to ABP in vitro and represents a major etiological factor for human liver cancer, I investigated a potential role for oxidative stress in our ABP carcinogenesis model. Using a hepatoma cell line, I found that the N-hydroxylation of ABP by CYP2E1 induced oxidative stress. Following in vivo exposure to ABP, I detected increased oxidative stress in male wild-type but not in male Cyp2e1(-/-) or female mice. On the other hand, a stronger antioxidant response was observed in females, which may protect them from ABP-induced oxidative stress and subsequent liver carcinogenesis. |
