Vol. 281, Issue 1, 464-469, 1997

Influence of the Vitamin D Status on the Early Hepatic Response to Carcinogen Exposure in Rats¹

Ru-Kun He and Marielle Gascon-Barré

Centre de Recherche Clinique André-Viallet, Hôpital Saint-Luc (R.-K.H., M.G.-B.), and Département de Pharmacologie, Faculté de Médecine, Université de Montréal (M.G.-B.), Montréal, Canada

Although 1,25-dihydroxyvitamin D₃ has been shown to promote the differentiation of cancer cells and cell lines in vitro, its protective effect against a chemical insult known to induce neoplastic growth in vivo has not been evaluated. The aim of this study was to investigate, in vivo, the influence of the vitamin D status on the early response to an insult known to induce morphological and functional changes leading to hepatocarcinogenesis. The influence of vitamin D status on the susceptibility of rat liver to carcinogenesis was studied after the administration of diethylnitrosamine and 2-acetylaminofluorene, in association with a partial hepatectomy (Solt-Farber protocol), to normal or vitamin D-depleted rats. Preneoplastic foci (-glutamyltranspeptidase-positive and glucose-6-phosphatase-negative) appeared in both groups of animals as early as 1 week after 2-acetylaminofluorene withdrawal and continued to increase during the subsequent weeks. Livers from vitamin D-depleted rats exhibited a significant increase in the number of foci over that observed in normal rats at weeks 1 and 5 after 2-acetylaminofluorene withdrawal. However, the main effect of vitamin D depletion was on focus size, which was found to be significantly greater in vitamin D-depleted rat livers at weeks 2 to 6; focus area (volume fraction) was also found to be consistently larger in livers of vitamin D-depleted rats than in those of normal rats. Labeling of oval cells, a cell compartment possibly associated with the repopulation of the liver parenchyma, was significantly reduced by vitamin D depletion. Control rat livers of both groups showed normal liver histology, and no foci, nodules or oval cells were detected in either group. The present data suggest that vitamin D depletion leads to increased in vivo susceptibility to chemicals known to induce hepatocarcinogenesis. Long-term studies must be conducted to evaluate the effect of vitamin D status on the evolution of preneoplastic foci into frank hepatocellular carcinoma.