Carcinogenesis, Vol 19, 403-411, Copyright © 1998 by Oxford University Press
S Gradelet, AM Le Bon, R Berges, M Suschetet and P Astorg
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.
ARTICLES
Dietary carotenoids inhibit aflatoxin B1-induced liver preneoplastic foci and DNA damage in the rat: role of the modulation of aflatoxin B1 metabolism
Institut National de la Recherche Agronomique, Unite de Toxicologie Nutritionelle, Dijon, France.
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