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 prog ression phase of hepatocarcinogenesis were evaluated in this study. For thi s purpose, male Wistar rats were first submitted to the resistant hepatocyt e model of carcinogenesis (diethylnitrosamine for initiation and 2-acetylam inofluorene for selection/promotion). Ten months after initiation, the anim als were distributed into four groups and treated by gavage, every other da y and during eight weeks, with corn oil (control group), vitamin A (10 mg/k g of body wt), all-trans retinoic acid (10 mg/kg body wt), or 9-cis retinoi c acid (10 mg/kg body wt). After this period, the animals were killed one h our after intraperitoneal administration of 5-bromo-2-deoxyuridine (BrdU, 1 00 mg/kg body wt). At the time of sacrifice, liver samples were collected f or histopathological (hematoxylin-eosin) examination and immunohistochemica l detection of glutathione S-transferase and BrdU as well as for analysis o f retinol and retinoic acid concentrations. Histopathological examination s howed the lowest incidence of hepatocarcinomas in vitamin A-treated animals . Moreover, groups treated with retinoids demonstrated lower hepatic BrdU l abeling indexes in the neoplastic lesions, as well as in their respective s urrounding tissues, than controls. Thus vitamin A and all-trans and 9-cis r etinoic acid strongly inhibited cell proliferation when administered during the progression phase of hepatocarcinogenesis. Therefore, the anticarcinog enic effects that have been attributed to these retinoids could be partiall y related to their capacity of inhibiting in vivo cell proliferation.