Studied on cerebellar haem metabolism in the rat in vivo.
Rats were injected intraventricularly with 5-amino[4-14C]laevulinate and the radioactivity recovered in the total cerebellum homogenate and in its haem and porphyrin fractions was determined in time. Two phases could be distinguished in the decline of haem radioactivity, suggesting labelling of at least two pools of widely different turnover rates. Succinyl acetone, when injected intraventricularly, caused a marked and long-lasting inhibition of cerebellar 5-aminolaevulinate dehydratase activity and a corresponding inhibition of the incorporation of [14C]5-aminolaevulinate into cerebellar haem in vivo. Inhibition of cerebellar haem biosynthesis by succinylacetone was followed by stimulation of the first enzyme of the pathway, 5-aminolaevulinate synthase, whereas intraventricular injection of haematin led to a significant depression of the activity of the enzyme. This suggested that the cerebellar 5-aminolaevulinate synthetase is regulated by haem through a negative feedback mechanism. Rats given repeated doses of succinylacetone, so as to maintain 80% inhibition of their cerebellar 5-aminolaevulinate dehydratase activity for 5 days, failed to exhibit any obvious symptoms of toxicity but became more sensitive to the neurotoxic effects of large intraventricular doses of 5-aminolaevulinate.
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000622:Aminolevulinic Acid / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D005246:Feedback; D006418:Heme / Q000096:biosynthesis*; D006537:Heptanoates / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D000623:Porphobilinogen Synthase / Q000037:antagonists & inhibitors; D011166:Porphyrins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
D006537:Heptanoates; D011166:Porphyrins; D006418:Heme; C020804:succinylacetone; D000622:Aminolevulinic Acid; D000624:5-Aminolevulinate Synthetase; D000623:Porphobilinogen Synthase