Polychlorinated biphenyls: in vivo and in vitro modifications of cholesterol and fatty acid biosynthesis.
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.
D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000096:biosynthesis*; D002951:Citrates / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis*; D005260:Female; D066298:In Vitro Techniques; D008099:Liver / Q000033:anatomy & histology / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D051381:Rats
D002951:Citrates; D005227:Fatty Acids; D004247:DNA; D002784:Cholesterol; D011078:Polychlorinated Biphenyls; D064429:Fatty Acid Synthases; D000103:Acetyl-CoA Carboxylase; D008798:Mevalonic Acid