Vitamin A and all-trans and 9-cis retinoic acids inhibit cell proliferation during the progression phase of hepatocarcinogenesis in Wistar rats

The effects of vitamin A and all-trans and 9-cis retinoic acids on the progression phase of hepatocarcinogenesis were evaluated in this study. For this purpose, male Wistar rats were first submitted to the resistant hepatocyte model of carcinogenesis (diethylnitrosamine for initiation and 2-acetylaminofluorene for selection/promotion). Ten months after initiation, the animals were distributed into four groups and treated by gavage, every other day and during eight weeks, with corn oil (control group), vitamin A (10 mg/kg of body wt), all-trans retinoic acid (10 mg/kg body wt), or 9-cis retinoic acid (10 mg/kg body wt). After this period, the animals were killed one hour after intraperitoneal administration of 5-bromo-2-deoxyuridine (BrdU, 100 mg/kg body wt). At the time of sacrifice, liver samples were collected for histopathological (hematoxylin-eosin) examination and immunohistochemical detection of glutathione S-transferase and BrdU as well as for analysis of retinol and retinoic acid concentrations. Histopathological examination showed the lowest incidence of hepatocarcinomas in vitamin A-treated animals. Moreover, groups treated with retinoids demonstrated lower hepatic BrdU labeling indexes in the neoplastic lesions, as well as in their respective surrounding tissues, than controls. Thus vitamin A and all-trans and 9-cis retinoic acid strongly inhibited cell proliferation when administered during the progression phase of hepatocarcinogenesis. Therefore, the anticarcinogenic effects that have been attributed to these retinoids could be partially related to their capacity of inhibiting in vivo cell proliferation.