Low hepatic glutathione S-transferase and increased hepatic DNA adduction contribute to increased tumorigenicity of aflatoxin B 1 in newborn and partially hepatectomized mice

Abstract

Low levels of hepatic glutathione S-transferase and increased formation of aflatoxin B 1 (AFB 1)–DNA adducts correlate with hepatocyte proliferation and increased hepatocarcinogenesis in both newborn mice and partially hepatectomized adult mice, as compared to normal, adult C57BL/6J mice. Newborn mice, which are highly susceptible to the hepatocarcinogenic effects of AFB 1, have active proliferation of hepatocytes until 3 weeks of age, when hepatocyte proliferation abruptly ceases. At about this time, the mice become highly resistant to AFB 1. In adult mice, AFB 1 carcinogenicity is increased after stimulation of liver proliferation by partial hepatectomy. To become carcinogenic, AFB 1 is activated in the liver by the P450 enzyme system to electrophilic intermediates, some of which form DNA adducts believed to be responsible for mutations leading to cancer. The most carcinogenic intermediate, AFB 1-8,9-epoxide, is detoxified by glutathione S-transferase-mediated conjugation to glutathione. Glutathione levels, glutathione S-transferase levels, and AFB 1–DNA adduct formation were measured at 4, 10, 30, 120, 245 and 365 days of age in C57BL/6J mice. There was a 5-fold increase in hepatic glutathione S-transferase levels and 13-fold decrease in hepatic AFB 1–DNA adduct formation over these ages. Induction of hepatocyte proliferation following partial hepatectomy of 120-day-old mice lowered hepatic glutathione S-transferase levels and increased the extent of hepatic AFB 1–DNA formation to levels similar to those measured in 4-day-old mice. These results indicate that increased susceptibility to AFB 1 hepatocarcinogenesis in newborn mice, and in adult mice following partial hepatectomy, is due to decreased GST and increased adduct formation in proliferating liver.