POLYCHLORINATED BIPHENYLS - INVIVO AND INVITRO MODIFICATIONS OF CHOLESTEROL AND FATTY-ACID BIOSYNTHESIS

  • 1 January 1978
    • journal article
    • research article
    • Vol. 1  (6) , 813-828
Abstract
Aroclor 1254 (0.1% wt/wt) administered in the rats'' 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 and 26% after 14 and 30 days, respectively. Biosynthesis of cholesterol from [2-14C]acetate and [2-14C]mevalonate was decreased by 51 and 31%, 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]acetate to fatty acids was decreased 43% by Aroclor 1254 (0.1% wt/wt, dietary) and 73% by Arocolor 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 polychlorinated biphenyl. Citrate cleavage enzyme was inhibited by Aroclor 1254. When ATP and citrate concentrations were varied, the Ki were 5.3 .times. 10-5 M and 11.5 .times. 10-5 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.