Low hepatic glutathione S-transferase and increased hepatic DNA adduction contribute to increased tumorigenicity of aflatoxin B1 in newborn and partially hepatectomized mice.
Low levels of hepatic glutathione S-transferase and increased formation of aflatoxin B1 (AFB1)-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 AFB1, 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 AFB1. In adult mice, AFB1 carcinogenicity is increased after stimulation of liver proliferation by partial hepatectomy. To become carcinogenic, AFB1 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 AFB1-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 AFB1-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 AFB1-DNA formation to levels similar to those measured in 4-day-old mice. These results indicate that increased susceptibility to AFB1 hepatocarcinogenesis in newborn mice, and in adult mice following partial hepatectomy, is due to decreased GST and increased adduct formation in proliferating liver.
Shupe
Thomas
T
Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Medical Science Building, P.O. Box 100275, Gainesville, FL 32610-0275, USA. shupe@pathology.ufl.edu
Sell
Stewart
S
D016604:Aflatoxin B1 / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000503:physiopathology; D018736:DNA Adducts; D005982:Glutathione Transferase / Q000032:analysis* / Q000494:pharmacology; D006498:Hepatectomy; D022781:Hepatocytes / Q000502:physiology; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000503:physiopathology; D051379:Mice
D018736:DNA Adducts; D016604:Aflatoxin B1; D005982:Glutathione Transferase