Toxicity of valproic acid in mice with decreased plasma and tissue carnitine stores.
Weanling rats were fed a simple riboflavin-deficient diet or the same diet supplemented with galactoflavin. Oxidative phosphorylation was studied in isolated hepatic mitochondria. Throughout the course of the experimental diets, a total of 8 weeks, there were no alterations in the respiratory control ratios or in the ADP/O ratios of the isolated mitochondria. Succinate dehydrogenase activity decreased in the first 3 weeks of deficiency, but oxidation of succinate remained at a constant level. After 3 weeks, the State 3 oxidation rate for succinate and fl-hydroxybutyrate declined, while oxidation of pyruvate, glutamate, and cw-ketoglutarate was untiected. The most dramatic mitochondrial effect of riboflavin deficiency was on fatty acid oxidation. As early as 1 day after the deficient diet was begun, pahnitoyl-l-carnitine and hexanoate oxidation was decreased by 35%; by Day 6, this reduction was 55%, and by Day 28 it was 75%. These effects could not be reproduced by total starvation of the rats. To determine the biochemical basis of the decrease in the ability of mitochondria to oxidize fatty acids, the specific activity of the enzymes involved in fatty acid oxidation was measured. The mitochondrial defect depended in part on a reduction in acyl-CoA dehydrogenase actiyities. Of these dehydrogenases, butyryl-CoA dehydrogenase activity was depressed to the greatest extent. Alterations in electron transfer flavoprotein may also be involved in decreased capacity for fatty acid oxidation. Unlike the acyl-CoA dehydrogenases, the other enzymes of fatty acid oxidation were variably affected by riboflavin deficiency. Of these, carnitine palmitoyltransferase, fl-hydroxyacyl-CoA dehydrogenase, and fi-ketothiolase showed as much as a a-fold increase in specific activity.