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.

Effects of beta-carotene and vitamin A on oval cell proliferation and connexin 43 expression during hepatic differentiation in the rat(1).

The effects of beta-carotene and vitamin A administrations were evaluated in an in vivo model of hepatic cell differentiation. For this purpose, male Wistar rats received beta-carotene (70 mg/kg of body weight), vitamin A (10 mg/kg of body weight) or corn oil (control group), by gavage and at every other day during the entire experimental period. After 4 consecutive weeks of treatment, the animals were submitted to the AAF/PH model of hepatic cell differentiation (6 x 20 mg of AAF [2-acetylaminofluorene]/kg of body weight and partial hepatectomy) and killed on different days following the surgery (until day 16 after hepatectomy). Liver samples were collected for determination of beta-carotene, retinol and retinyl palmitate concentrations, for histopathological (hematoxilin-eosin) examination, for immunohistochemical detection of glutathione S-transferase, as well as for the evaluation of connexin 43 (a structural protein of gap junctions of oval cells) expression by northern blot analysis. Compared to controls, the oval cell proliferation peaks (observed by histopathological examination and immunohistochemistry) and connexin 43 expression peaks, were postponed to later days after hepatectomy, in a similar way in beta-carotene and vitamin A treated animals. Compared to the other experimental groups, the vitamin A treated group showed an increase in connexin 43 expression. It was concluded that beta-carotene and vitamin A modulated oval cell proliferation and connexin 43 expression, delaying both events. These findings suggest that beta-carotene and vitamin A can modulate the hepatic differentiation process in vivo.