Abstract 4161: Synergistic effects of aflatoxin B1 exposure and glycine N-methyltransferase deficiency in hepatocarcinogenesis

Abstract

Abstract In both humans and rodents, males are known to be more susceptible than females to hepatocarcinogenesis. We have previously reported that glycine N-methyltransferase (GNMT) interacts with aflatoxin B1 (AFB1) and reduces both AFB1-DNA adduct formation and hepatocellular carcinoma (HCC) in mice. We also reported that 50% of the males and 100% of the females in a small group of Gnmt null (Gnmt−/−) mice developed HCC, with first liver nodules detected at mean ages of 17 and 16.5 months, respectively. In this study we tested our hypothesis that male and female Gnmt−/− mice are susceptible to AFB1 carcinogenesis, and that the absence of Gnmt expression may accelerate AFB1-induced liver tumorigenesis. We inoculated Gnmt−/− and wild-type mice intraperitoneally with AFB1 at 7 days and 9 weeks of age and periodically examined them using ultrasound. Liver nodules were detected in 6 of 8 males and 5 of 5 females at 12.7 and 12 months of ages, respectively. Liver nodules from 5/8 (62.5%) male and 4/5 (80%) female Gnmt−/− mice were diagnosed as having HCC, approximately 6 months earlier than AFB1-treated wild-type mice. Results from microarray and real-time PCR analyses indicate that five detoxification pathway-related genes were down-regulated in AFB1-treated Gnmt−/− mice: Cyp1a2, Cyp3d44, Cyp2d22, Gsta1 and Abca8a. In summary, we observed a synergistic relationship between GNMT deficiency and AFB1 exposure in hepatocarcinogenesis, further evidence that GNMT over-expression is an important contributing factor to female liver cancer resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4161.