Protection of rats by clofibrate against the hypoglycaemic and toxic effects of hypoglycin and pent-4-enoate. An ultrastructural and biochemical study.
An ultrastructural and biochemical study of the toxic and hypoglycaemic effects of hypoglycin and pent-4-enoate was made on the livers of normal and clofibrate-fed rats. Injection of hypoglycin to rats doubles (from 22% to 44%) the volume fraction of mitochondria and decreases (from 1.05% to 0.26%) the volume fraction of peroxisomes in hepatocytes. The fast-acting toxin pent-4-enoate causes few ultrastructural changes except for the accumulation of lipids. In male adult rats fed with 0.5% clofibrate in their diet for 1-2 months, the volume fraction occupied by peroxisomes and mitochondria in hepatocytes rose to 6.26% and 29.5% respectively. Clofibrate feeding apparently protected the animals against the toxic, hypoglycaemic and hypothermic effects of hypoglycin and of pent-4-enoate, and completely prevented the ultrastructural damage caused by hypoglycin. After hypoglycin administration, hepatic mitochondrial butyryl-CoA dehydrogenase activity was inhibited by more than 90% and, surprisingly, the activity of the peroxisomal enzymes studied was largely preserved. When hypoglycin was given to rats fed on a clofibrate-containing diet, the oxidation of decanoylcarnitine, which was incomplete after hypoglycin treatment alone, remained incomplete with uncoupled mitochondria, but became apparently complete with coupled mitochondria. In the latter condition, there was a slowing of the rate during the last quarter of the pulse of oxygen uptake. Further, butyryl-CoA dehydrogenase activity was much less affected by hypoglycin in clofibrate-fed animals. Pent-4-enoate does not inhibit beta-oxidation in coupled mitochondria from clofibrate-treated rats.
D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D002994:Clofibrate / Q000494:pharmacology*; D003521:Cyclopropanes / Q000009:adverse effects*; D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated / Q000009:adverse effects*; D007003:Hypoglycemia / Q000139:chemically induced*; D007005:Hypoglycins / Q000009:adverse effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008830:Microbodies / Q000378:metabolism; D008854:Microscopy, Electron; D008930:Mitochondria, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains
D003521:Cyclopropanes; D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated; D007005:Hypoglycins; C002893:decanoylcarnitine; C041757:hypoglycin; C009785:4-pentenoic acid; D002994:Clofibrate; D002331:Carnitine