INFLUENCE OF THE VITAMIN-D STATUS ON THE EARLY HEPATIC RESPONSE TO CARCINOGEN EXPOSURE IN RATS

Although 1,25-dihydroxyvitamin D-3 has been shown to promote the diffe rentiation of cancer cells and cell lines in vitro, its protective eff ect against a chemical insult known to induce neoplastic growth in viv o 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 sus ceptibility of rat liver to carcinogenesis was studied after the admin istration of diethylnitrosamine and 2-acetylaminofluorene, in associat ion with a partial hepatectomy (Solt-Farber protocol), to normal or vi tamin D-depleted rats. Preneoplastic foci (gamma-glutamyltranspeptidas e-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 vit amin 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-acety laminofluorene withdrawal. However, the main effect of vitamin D deple tion 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 fra ction) 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 liv er parenchyma, was significantly reduced by vitamin D depletion. Contr ol rat livers of both groups showed normal liver histology, and no foc i, nodules or oval cells were detected in either group. The present da ta suggest that vitamin D depletion leads to increased in vivo suscept ibility to chemicals known to induce hepatocarcinogenesis. Long-term s tudies must be conducted to evaluate the effect of vitamin D status on the evolution of preneoplastic foci into frank hepatocellular carcino ma.