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  • Title: Polychlorinated biphenyls: in vivo and in vitro modifications of cholesterol and fatty acid biosynthesis.
    Author: Kling D, Kunkle J, Roller AS, Gamble W.
    Journal: J Environ Pathol Toxicol; 1978; 1(6):813-28. PubMed ID: 32219.
    Abstract:
    Aroclor 1254 (0.1 percent w/w) administered in the diet caused moderate to severe vacuolar degeneration of periportal hepatocytes, heptocyte enlargement, lipid accumulation, and necrosis of the liver. The incorporation of [2-14C]mevalonate into nonsaponifiable lipids was inhibited 18 percent and 26 percent after 14 days and 30 days, respectively. Biosynthesis of cholesterol from [2-14C]acetate and [2-14C]mevalonate was decreased by 51 percent and 31 percent respectively after 30 days, but no significant inhibition was observed after 14 days of feeding Aroclor 1254. [2-14C]Acetate incorporation into non-saponifiable lipids was 1.66 times greater in homogenates from Aroclor-treated rats than in those from control rats. Similar results were obtained when 3H2O, Mevalonate-14C, and acetate-2-14C were incubated in vivo. The conversion of [2-14C-A1acetate to fatty acids was decreased 43 percent by Aroclor 1254 (0.1 percent w/w, dietary) and 73 percent by Aroclor 1254, 500 ppm, in vitro. The in vitro incorporation of each [2-14C]acetate, [2-14C]mevalonate and [1-14C]isopentenyl pyrophosphate into cholesterol was inhibited by Aroclor 1254. There was no inhibition of the conversion of [1-14C]mevalonate to CO2, indicating that there was no inhibition of mevalonate-5-pyrophosphate anhydrodecarboxylase. Fatty acid synthase was not inhibited by PCB. Citrate cleavage enzyme was inhibited by Aroclor 1254. When ATP and citrate concentrations were varied, the Ki's were 5.3 X 10(-5)M and 11.5 X 13(-5)M, respectively. Acetyl CoA carboxylase activity was not inhibited by 1000 ppm Aroclor 1254 in vitro. Inhibition of citrate cleavage enzyme is a possible explanation for the observed decrease in fatty acid synthesis. There was an apparent diversion of acetate from fatty acid synthesis into the formation of non-saponifiable lipids, accompanied by an inhibition of the biosynthesis of cholesterol per se.
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