Inhibitory effects of beta-carotene and vitamin A during the progression phase of hepatocarcinogenesis involve inhibition of cell proliferation but not alterations in DNA methylation

The inhibitory effects of beta-carotene and vitamin A administered to rats in the progression phase of the resistant hepatocyte model of hepatocarcinogenesis were investigated. beta-Carotene- and vitamin A-treated animals tended to present, with a lower incidence of hepatic cancers than controls at sacrifice. Vitamin A, but not beta-carotene, administration also tended to reduce the total number of persistent hepatocyte nodules. Histological examination of sections stained with hematoxylin and eosin confirmed these results. This suggests that both compounds exhibit inhibitory effects during conversion of persistent nodules to cancers, whereas only the retinoid is also capable of inhibiting the evolution of persistent nodules or causing them to regress. Moreover, beta-carotene- and vitamin A-treated animals showed lower hepatic bromodeoxyuridine labeling indexes in neoplastic lesions as well as in adjacent normal tissues than controls, suggesting an inhibitory action of these substances on cell proliferation. However, neither beta-carotene nor vitamin A administration resulted in substantial alterations in the CCGG sequence methylation pattern of hydroxymethylglutaryl coenzyme A reductase, c-myc, and c-Ha-ras genes, the products of which are related to cell proliferation and carcinogenesis. Therefore, these inhibitory effects of beta-carotene and vitamin A on progression of hepatocarcinogenesis do not seem to be related to DNA methylation.