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 liver carcinogenesis 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 were injected 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 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 carotenoids or of 3-MC on AFB1-induced liver DNA damage were evaluated using different endpoints: liver DNA single-strand breaks (SSB) induced by AFB1, and in vivo binding of [3H]AFB1 to liver DNA and plasma albumin. Finally, the modulation of AFB1 metabolism by carotenoids or by 3-MC was investigated in vitro by incubating [14C]AFB1 with liver 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 size of liver preneoplastic foci. In a similar way as 3-MC, the P4501A-inducer carotenoids, beta-apo-8'-carotenal astaxanthin and canthaxanthin, decreased in vivo AFB1-induced DNA SSB and the binding of AFB1 to liver DNA and plasma albumin, and increased in vitro AFB1 metabolism to aflatoxin M1, a less genotoxic metabolite. It is concluded that these carotenoids exert their protective effect through the deviation of 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 protective effect against the initiation of liver preneoplastic foci by AFB1 is mediated by other mechanisms.
Gradelet
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Institut National de la Recherche Agronomique, Unité de Toxicologie Nutritionelle, Dijon, France.
Le Bon
A M
AM
Bergès
R
R
Suschetet
M
M
Astorg
P
P
D016604:Aflatoxin B1 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity; D002338:Carotenoids / Q000494:pharmacology*; D004249:DNA Damage; D004032:Diet; D008114:Liver Neoplasms, Experimental / Q000517:prevention & control*; D008297:Male; D008748:Methylcholanthrene / Q000633:toxicity; D008862:Microsomes, Liver / Q000378:metabolism; D011230:Precancerous Conditions / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000378:metabolism; D014801:Vitamin A / Q000494:pharmacology
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D012709:Serum Albumin; D014801:Vitamin A; D002338:Carotenoids; D008748:Methylcholanthrene; D016604:Aflatoxin B1