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The protective effect of beta-carotene and vitamin A on genotoxicity and cytotoxicity of dimethylnitrosamine in vitamin A-deficient rats Yee, Gina


Epidemiological evidence and chemopreventive trials point to an antimutagenic and anticarcinogenic role for retinoids and carotenoids. Studies on human populations are logistically difficult and often ethically unacceptable. Therefore, to gain information on the potential chemopreventive benefits of dietary vitamin A and beta-carotene, the following experimental model was used. Rats were made vitamin A (retinol) deficient, then exposed to the liver carcinogen dimethylnitrosamine (DMN), partially hepatectomized, and thereafter, examined for the extent of liver necrosis (cytotoxicity) and the frequency of anaphase and telophase cells with chromosomal fragments, chromatin bridges and micronuclei (genotoxicity). Vitamin A-deficient rats (serum retinol levels <2 0 ng/ml and liver retinol levels <43 ng/g tissue) showed increased sensitivity towards the cytotoxic and genotoxic action of DMN as compared to vitamin A-fed dietary control rats. This elevated sensitivity was abolished by supplementation of the vitamin A-deficient diet with beta-carotene (10 mg/kg diet) or with vitamin A (2 mg/kg diet) prior to DMN exposure. However, vitamin A feeding at higher doses (16 mg/kg diet), which led to an excessive accumulation of retinol in the liver (>25,000 ng/g tissue), resulted in an accentuation of the necrotic and genotoxic action of DMN when high doses (35 mg/kg body weight) were administered. The results show that vitamin A deficiency leads to an increased susceptability to DMN-induced damage. Dietary supplementation with beta-carotene and with vitamin A (at adequate levels) protected against the deleterious effects of DMN, but supplementation with vitamin A at excessive levels potentiated the action of the carcinogen. This divergent, dose-dependent action of vitamin A calls for caution in the design of intervention strategies.

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