Inhibition of lipogenesis by halothane in isolated rat liver cells.
1. Halothane at clinically effective concentrations [2.5 and 4% (v/v) of the gas phase of the incubation flask] was found to inhibit significantly lipogenesis from endogenous substrates, e.g., glycogen, or from added lactate plus pyruvate. This was accompanied by a decrease in the ratio of the free [NAD+]/[NADH] of the mitochondrion and the cytoplasm, as shown by the [3-hydroxybutyrate]/[acetoacetate] ratio and the [lactate]/[pyruvate] ratio. 2. Acetoacetate or pyruvate decreased the inhibitory effect of halothane and restored lipogenesis to control rates. They were reduced rapidly by 3-hydroxybutyrate dehydrogenase or lactate dehydrogenase respectively, with the concomitant oxidation of NADH and the generation of NAD+. 3. These results suggest that the mechanism by which halothane inhibits lipogenesis from glycogen or lactate is by inhibition of the oxidation of NADH; this results in inhibition of flux of carbon through pyruvate dehydrogenase and a shortage of acetyl-CoA for fatty acid synthesis. Thus when NADH acceptors are added in the presence of halothane, the concentration of mitochondrial NAD+ is raised so that the flux of carbon through pyruvate dehydrogenase increases and lipogenesis is restored.
D000090:Acetoacetates / Q000378:metabolism; D000818:Animals; D005227:Fatty Acids / Q000096:biosynthesis*; D006221:Halothane / Q000494:pharmacology*; D066298:In Vitro Techniques; D007773:Lactates / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008112:Liver Glycogen / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D011773:Pyruvates / Q000378:metabolism; D051381:Rats
D000090:Acetoacetates; D005227:Fatty Acids; D007773:Lactates; D008112:Liver Glycogen; D011773:Pyruvates; D009243:NAD; D006221:Halothane