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Chemoprevention of Aflatoxin B₁ Hepatocarcinogenesis by Coumarin, a Natural Benzopyrone That Is a Potent Inducer of Aflatoxin B₁-Aldehyde Reductase, the Glutathione S-Transferase A5 and P1 Subunits, and NAD(P)H:Quinone Oxidoreductase in Rat Liver¹

Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland [V. P. K., E. M. E., S. A. C., R. M., J. D. H.]; Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Leicester LE1 9HN, England [M M. M., D. J. J., G. E. N.]; Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK10 4TJ, England [G. J. M.], United Kingdom

Structurally diverse compounds can confer resistance to aflatoxin B₁ (AFB₁) hepatocarcinogenesis in the rat. Treatment with either phytochemicals [benzyl isothiocyanate, coumarin (CMRN), or indole-3-carbinol] or synthetic antioxidants and other drugs (butylated hydroxyanisole, diethyl maleate, ethoxyquin, ß-naphthoflavone, oltipraz, phenobarbital, or trans-stilbene oxide) has been found to increase hepatic aldo-keto reductase activity toward AFB₁-dialdehyde and glutathione S-transferase (GST) activity toward AFB₁-8,9-epoxide in both male and female rats. Under the conditions used, the natural benzopyrone CMRN was a major inducer of the AFB₁ aldehyde reductase (AFAR) and the aflatoxin-conjugating class- GST A5 subunit in rat liver, causing elevations of between 25- and 35-fold in hepatic levels of these proteins. Induction was not limited to AFAR and GSTA5: treatment with CMRN caused similar increases in the amount of the class- GST P1 subunit and NAD(P)H:quinone oxidoreductase in rat liver. Immunohistochemistry demonstrated that the overexpression of AFAR, GSTA5, GSTP1, and NAD(P)H:quinone oxidoreductase affected by CMRN is restricted to the centrilobular (periacinar) zone of the lobule, sometimes extending almost as far as the portal tract. This pattern of induction was also observed with ethoxyquin, oltipraz, and trans-stilbene oxide. By contrast, induction of these proteins by ß-naphthoflavone and diethyl maleate was predominantly periportal. Northern blotting showed that induction of these phase II drug-metabolizing enzymes by CMRN was accompanied by similar increases in the levels of their mRNAs. To assess the biological significance of enzyme induction by dietary CMRN, two intervention studies were performed in which the ability of the benzopyrone to inhibit either AFB₁-initiated preneoplastic nodules (at 13 weeks) or AFB₁-initiated liver tumors (at 50 weeks) was investigated. Animals pretreated with CMRN for 2 weeks prior to administration of AFB₁, and with continued treatment during exposure to the carcinogen for a further 11 weeks, were protected completely from development of hepatic preneoplastic lesions by 13 weeks. In the longer-term dietary intervention, treatment with CMRN before and during exposure to AFB₁ for a total of 24 weeks was found to significantly inhibit the number and size of tumors that subsequently developed by 50 weeks. These data suggest that consumption of a CMRN-containing diet provides substantial protection against the initiation of AFB₁ hepatocarcinogenesis in the rat.

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