Dietary carotenoids inhibit aflatoxin B1-induced liver preneoplastic foci and DNA damage in the rat: role of the modulation of aflatoxin B1 metabolism

To study the effects of carotenoids on the initiation of livercarcinogenesis by aflatoxin B1 (AFB1), male weanling rats were fed beta-carotene, beta-apo-8'-carotenal, canthaxanthin, astaxanthin or lycopene(300 mg/kg diet), or an excess of vitamin A (21000 RE/kg diet), or wereinjected i.p. with 3-methylcholanthrene (3-MC) (6 x 20 mg/kg body wt)before and during i.p. treatment with AFB1 (2 x 1 mg/kg body wt). The ratswere later submitted to 2-acetylaminofluorene treatment and partialhepatectomy, and placental glutathione S-transferase-positive liver fociwere detected and quantified. The in vivo effects of carotenoids or of 3-MCon AFB1-induced liver DNA damage were evaluated using different endpoints:liver DNA single-strand breaks (SSB) induced by AFB1, and in vivo bindingof [3H]AFB1 to liver DNA and plasma albumin. Finally, the modulation ofAFB1 metabolism by carotenoids or by 3-MC was investigated in vitro byincubating [14C]AFB1 with liver microsomes from rats that had been fed withcarotenoids or treated by 3- MC, and the metabolites formed by HPLC wereanalyzed. In contrast to lycopene or to an excess of vitamin A, both ofwhich had no effect, beta-carotene, beta-apo-8'carotenal, astaxanthin andcanthaxanthin, as well as 3-MC, were very efficient in reducing the numberand the size of liver preneoplastic foci. In a similar way as 3-MC, theP4501A- inducer carotenoids, beta-apo-8'-carotenal astaxanthin andcanthaxanthin, decreased in vivo AFB1-induced DNA SSB and the binding ofAFB1 to liver DNA and plasma albumin, and increased in vitro AFB1metabolism to aflatoxin M1, a less genotoxic metabolite. It is concludedthat these carotenoids exert their protective effect through the deviationof AFB1 metabolism towards detoxication pathways. In contrast,beta-carotene did not protect hepatic DNA from AFB1-induced alterations,and caused only minor changes of AFB1 metabolism: seemingly, its protectiveeffect against the initiation of liver preneoplastic foci by AFB1 ismediated by other mechanisms.