Abstract
The effect of carbon tetrachloride (CCl4) on aflatoxin B1 (AFB1)-induced enzyme altered hepatic foci has been examined in young male Fischer rats given AIN-76A diet. A single i.p. dose of AFB1 (0.2 mg/kg body wt) was given to rats 24 h after partial hepatectomy. Two weeks later, CCl4 (0.8 ml/kg body wt) was injected i.p. once a week for 9 weeks. Animals were sacrificed 24 h after the last dose of CCl4 and glutathione S-transferase placental form (GST-P) and gamma-glutamyl transpeptidase (GGT) positive hepatic foci were analyzed by immunohistochemical and histochemical methods, respectively. Ten weeks after AFB1 dosing, treatment with CCl4 increased the number of AFB1-induced enzyme altered foci several fold and produced a ten to twenty-fold increase in area and volume. GST-P was more sensitive than GGT in detecting AFB1-induced enzyme altered foci. Treatment with AFB1 or CCl4 produced mild hepatic fibrosis in zones 1 and 3 respectively, whereas both treatments produced severe fibrosis in zones 1 to 3 areas. Treatment with CCl4 after AFB1 dosing lowered hepatic GSH levels by 20% and increased lipid peroxidation by 40%. It appears that CCl4, by being an effective enhancer of AFB1-induced enzyme altered hepatic foci in the rat, may mimic cirrhosis observed in human hepatocellular carcinoma.
Highlights
On the basis of epidemiological data, it has been established that one of the factors responsible for human liver cancer is aflatoxin B1 (AFB1), a mycotoxin produced by Aspergillus flavus (IARC Monographs, 1993)
Even though a rat is the most susceptible laboratory animal species to AFB1 hepatocarcinogenesis (Newberne and Butler, 1969; Eaton and Gallagher, 1994), cirrhosis is not observed in this species even in the presence of various promoters including phenobarbital (Newberne and Butler, 1969; KrauppGrasl et al, 1990; Hiruma et al, 1997)
Previous studies with diethylnitrosamine and AFB1 have indicated that early glutathione Stransferase placental form (GST-P) positive hepatocytes induced by these carcinogens are the precursors for preneoplastic foci and nodules (Moore et al, 1987; Satoh et al, 1989; Tsuji et al, 1992; Dragan et al, 1994; Hiruma et al, 1996, 1997)
Summary
On the basis of epidemiological data, it has been established that one of the factors responsible for human liver cancer is aflatoxin B1 (AFB1), a mycotoxin produced by Aspergillus flavus (IARC Monographs, 1993). Compensatory cell proliferation induced by either partial hepatectomy (PH) or carbon tetrachloride (CCl4) plays an important role in the initiation of rat liver carcinogenesis by various chemicals including AFB1 as examined by enzyme altered foci (Warwick, 1971; Cayama et al, 1978; Pitot et al, 1978; Columbano et al, 1987; Hiruma et al, 1996). Repeated administration of CCl4 to rats, has enhanced nitrosamine-induced formation of enzyme altered hepatic foci and nodules (Columbano et al , 1990; Zalatnai et al, 1991; Cho and Jang, 1993). It is known that repeated administration of CCl4 to rats results in cirrhosis of the liver (PerezTamayo, 1983; Gasso et al, 1996)
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