J Pharm Pharmacogn Res 2(Suppl. 1): S110, 2014
Special supplement with the abstract book of LATINFARMA 2013
C 040: USE OF GENETICALLY MODIFIED MOUSE MODELS TO STUDY MECHANISMS OF CHEMICALLY-INDUCED LIVER CANCER RISK
Grant DM.Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada.
Liver cancer is the 5th most common malignancy and the 3rd most common cause of cancer-related death, reflecting a very poor 5-year survival rate of less than 20%. Major liver cancer risk factors include hepatitis B/C infection, liver cirrhosis and obesity, which produce a tumor growth promoting, pro-inflammatory pathological state. However, liver cancer risk has also been linked to exposure to certain genotoxic environmental chemicals, of which the most widely used liver-selective carcinogens in experimental rodent studies are the aromatic amine 4-aminobiphenyl (ABP) and the nitrosamine diethylnitrosamine (DEN). Studies in our laboratory are aimed at utilizing genetically modified mice to investigate the contributions of carcinogen bioactivation, DNA damage, oxidative stress, cellular damage and inflammatory responses to the carcinogenicity of ABP and DEN. We compared the tumorigenicity of ABP in postnatally exposed male and female wild-type and arylamine N-acetyltransferase (NAT)deficient mice, and we observed that male NAT-deficient mice were significantly protected against eventual tumor growth and female mice were tumor-resistant regardless of strain. However, these differences in tumor incidence did not correlate with differences in measures of acute ABP-induced DNA damage or mutations, suggesting that the sex and strain differences in tumor incidence are driven by events that are independent of the genotoxicity of ABP. ABP and DEN produced no acute hepatotoxicity at tumor-inducing doses in either sex or strain, and only DEN produced a modest acute elevation in the proinflammatory cytokine IL-6. We are currently conducting studies to compare the time course of chronic hepatotoxic, oxidative stress inducing, pro-inflammatory and proliferative effects of postnatal ABP and DEN exposure. Using CYP1A2-deficient mice, we have also recently discovered that at the tumorigenic doses of ABP that are commonly used in rodent studies, the cytochrome P450 isoform CYP2E1 is likely to be quantitatively more important than CYP1A2 in the bioactivation of ABP to its N-hydroxylated metabolite. Overall, we hope that our studies will shed light on the mechanisms that influence risk for liver tumor growth following chemical exposure, and lead to the identification of treatment or prevention measures for this disease in human at-risk populations.