In vivo studies of altered expression patterns of p53 and proliferative control genes in chronic vitamin A deficiency and hypervitaminosis.
Several clinical trials have revealed that individuals who were given beta-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 p21WAF1/CIF1 (by RT-PCR) in liver and lung of rats. This study showed that c-Jun levels were lower and that p53 and p21WAF1/CIF1 levels were higher in chronic vitamin A deficiency. Vitamin A supplementation increased expression of c-Jun, while decreasing the expression of p53 and p21WAF1/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.
Borrás
Elisa
E
Departamento de Bioquímica y Biología Molecular, Facultades de Medicina y Farmacia, Universidad de Valencia, Valencia, Spain.
Zaragozá
Rosa
R
Morante
María
M
García
Concha
C
Gimeno
Amparo
A
López-Rodas
Gerardo
G
Barber
Teresa
T
Miralles
Vicente J
VJ
Viña
Juan R
JR
Torres
Luis
L
D000818:Animals; D015153:Blotting, Western; D002455:Cell Division / Q000502:physiology; D002908:Chronic Disease; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004224:Diterpenes; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006986:Hypervitaminosis A / Q000139:chemically induced / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D046911:Macromolecular Substances; D011233:Precipitin Tests; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000084562:Retinyl Esters; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000032:analysis / Q000494:pharmacology*; D014802:Vitamin A Deficiency / Q000378:metabolism*
C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004224:Diterpenes; D046911:Macromolecular Substances; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D000084562:Retinyl Esters; D016159:Tumor Suppressor Protein p53; D014801:Vitamin A; C014794:retinol palmitate; D004247:DNA