DIETARY CAROTENOIDS INHIBIT AFLATOXIN B-1-INDUCED LIVER PRENEOPLASTICFOCI AND DNA-DAMAGE IN THE RAT - ROLE OF THE MODULATION OF AFLATOXIN B-1 METABOLISM

To study the effects of carotenoids on the initiation of liver carcino genesis by aflatoxin B-1 (AFB(1)), male weanling rats were fed beta-ca rotene, beta-apo-8'-carotenal, canthaxanthin, astaxanthin or lycopene (300 mg/kg diet), or an excess of vitamin A (21 000 RE/kg diet), or we re injected i.p. with 3-methylcholanthrene (3-MC) (6 x 20 mg/kg body w t) before and during i.p. treatment with AFB(1) (2 x 1 mg/kg body wt). The rats were later submitted to 2-acetylaminofluorene treatment and partial hepatectomy, and placental glutathione S-transferase-positive liver foci were detected and quantified. The in vivo effects of carote noids or of 3-MC on AFB(1)-induced liver DNA damage were evaluated usi ng different endpoints: liver DNA single-strand breaks (SSB) induced b y AFB(1), and in vivo binding of [H-3]AFB(1) to liver DNA and plasma a lbumin. Finally, the modulation of AFB(1) metabolism by carotenoids or by 3-MC was investigated in vitro by incubating [C-14]AFB(1) with liv er microsomes from rats that had been fed with carotenoids or treated by 3-MC, and the metabolites formed by HPLC were analyzed. In contrast to lycopene or to an excess of vitamin A, both of which had no effect , beta-carotene, beta-apo-8' carotenal, astaxanthin and canthaxanthin, as well as 3-MC, were very efficient in reducing the number and the s ize of liver preneoplastic foci. In a similar way as 3-MC, the P4501A- inducer carotenoids, beta-apo-8'-carotenal astaxanthin and canthaxanth in, decreased in vivo AFB(1)-induced DNA SSB and the binding of AFB(1) to liver DNA and plasma albumin, and increased in vitro AFB(1) metabo lism to aflatoxin M-1, a less genotoxic metabolite. It is concluded th at these carotenoids exert their protective effect through the deviati on of AFB(1) metabolism towards detoxication pathways. In contrast, be ta-carotene did not protect hepatic DNA from AFB(1)-induced alteration s, and caused only minor changes of AFB(1) metabolism: seemingly, its protective effect against the initiation of liver preneoplastic foci b y AFB(1) is mediated by other mechanisms.