Microtubules and the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase.
Cultured C-6 glial cells were utilized to evaluate the effect of antimicrotubular drugs on 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol synthesis. Colchicine, Colcemid, and vinblastine (1.0 muM) caused a marked reduction in HMG-CoA reductase activity and, as a consequence, the rate of cholesterol synthesis in these cells. No effect was observed with lumicolchicine, a mixture of colchicine isomers with no effect on microtubules. The effect of colchicine was apparent within 1 h after addition to the culture medium, and, after 6 h, HMG-CoA reductase activity in treated cells was only approximately 15 to 30% of that in untreated cells. Reductase activity was very sensitive to the concentration of drug added, i.e. cells treated with just 0.1 muM colchicine for 6 h exhibited a 50% lower enzymatic activity than did untreated cells. The lack of a generalized, nonspecific toxic effect on the cells was indicated by the finding of no change in the activities of fatty acid synthetase and NADPH-cytochrome c reductase and the rate of total protein synthesis in cells treated with colchicine (1 muM) for 6 h. A close temporal and quantitative correlation was observed between the effects of colchicine on HMG-CoA reductase and on a parameter of microtubular function, i.e. maintenance of glial cell shape. The data suggest that microtubules are involved in the regulation of HMG-CoA reductase and cholesterol synthesis in C-6 glial cells.
D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis; D003078:Colchicine / Q000494:pharmacology; D003703:Demecolcine / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000378:metabolism; D005910:Glioma; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D007700:Kinetics; D008870:Microtubules / Q000201:enzymology*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D051381:Rats; D014747:Vinblastine / Q000494:pharmacology
D014747:Vinblastine; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D009251:NADPH-Ferrihemoprotein Reductase; D064429:Fatty Acid Synthases; D003078:Colchicine; D003703:Demecolcine