Open AccessIn vivo studies of altered expression patterns of p53 and proliferative control genes in chronic vitamin A deficiency and hypervitaminosis
Author(s) -
Borrás Elisa,
Zaragozá Rosa,
Morante María,
García Concha,
Gimeno Amparo,
LópezRodas Gerardo,
Barber Teresa,
Miralles Vicente J.,
Viña Juan R.,
Torres Luis
Publication year - 2003
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1046/j.1432-1033.2003.03511.x
Subject(s) - vitamin a deficiency , medicine , vitamin , retinoic acid , endocrinology , calcitriol receptor , western blot , lewis lung carcinoma , biology , vitamin d and neurology , cancer , gene , retinol , biochemistry , metastasis
Several clinical trials have revealed that individuals who were given β−carotene and vitamin A did not have a reduced risk of cancer compared to those given placebo; rather, vitamin A could actually have caused an adverse effect in the lungs of smokers [Omenn, G.S., Goodman, G.E., Thornquist, M.D., Balmes, J., Cullen, M.R., Glass, A., Keogh, J.P., Meyskens, F.L., Valanis, B., Williams, J.H., Barnhart, S. & Hammar, S. N. Engl. J. Med (1996) 334 , 1150–1155; Hennekens, C.H., Buring, J.E., Manson, J.E., Stampfer, M., Rosner, B., Cook, N.R., Belanger, C., LaMotte, F., Gaziano, J.M., Ridker, P.M., Willet, W. & Peto, R. (1996) N. Engl. J. Med . 334 , 1145–1149]. Using differential display techniques, an initial survey using rats showed that liver RNA expression of c‐H‐Ras was decreased and p53 increased in rats with chronic vitamin A deficiency. These findings prompted us to evaluate the expression of c‐Jun , p53 and p21 WAF1/CIF1 (by RT‐PCR) in liver and lung of rats. This study showed that c‐Jun levels were lower and that p53 and p21 WAF1/CIF1 levels were higher in chronic vitamin A deficiency. Vitamin A supplementation increased expression of c‐Jun , while decreasing the expression of p53 and p21 WAF1/CIF1 . Western‐blot analysis demonstrated that c‐Jun and p53 showed a similar pattern to that found in the RT‐PCR analyses. Binding of retinoic acid receptors (RAR) to the c‐Jun promoter was decreased in chronic vitamin A deficiency when compared to control hepatocytes, but contrasting results were found with acute vitamin A supplementated cells. DNA fragmentation and cytochrome c release from mitochondria were analyzed and no changes were found. In lung, an increase in the expression of c‐Jun produced a significant increase in cyclin D1 expression . These results may explain, at least in part, the conflicting results found in patients supplemented with vitamin A and illustrate that the changes are not restricted to lung. Furthermore, these results suggest that pharmacological vitamin A supplementation may increase the risk of adverse effects including the risk of oncogenesis.