Cobalt inhibition of synthesis and induction of delta-aminolevulinate synthase in liver.
Cobalt has complex actions on the metabolism of heme in the liver. In this organ the metal potently induces heme oxygenase (EC 1.14.99.3), and decreases cellular heme and hemoprotein content. The metal also displays biphasic effects on hepatic heme synthesis. These effects are reflected in the ability of cobalt to initially inhibit synthesis of delta-aminolevulinate synthase [succinyl-CoA:glycine C-succinyltransferase (decarboxylating) EC 2.3.1.37], the rate limiting enzyme of the heme pathway, following which a later enhanced rate of formation of this enzyme occurs. In this study, cobalt was shown to block almost entirely the ability of the barbiturate analogue allylisopropylacetamide to induce delta-aminolevulinate synthase in liver. The blocking effect of cobalt on the otherwise potent enzyme inducing action of this drug was time-dependent; if the metal was injected 30 min prior to allylisopropylacetamide, inhibition of enzyme induction was complete. When the metal was administered 1.5 or more hours after allylisopropylacetamide, inhibition of enzyme induction was incomplete. Cobalt did not block the ability of the drug to directly degrade heme to "green pigment" thus the enzyme inducing action of allylisopropylacetamide and its degradative action on heme are separately mediated.
D000624:5-Aminolevulinate Synthetase / Q000096:biosynthesis*; D000502:Allylisopropylacetamide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D003035:Cobalt / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D006418:Heme / Q000378:metabolism; D011163:Hydroxymethylbilane Synthase / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008190:Lyases / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D011166:Porphyrins / Q000378:metabolism; D051381:Rats
D011166:Porphyrins; D000502:Allylisopropylacetamide; D003035:Cobalt; D006418:Heme; D006899:Mixed Function Oxygenases; D009251:NADPH-Ferrihemoprotein Reductase; D000624:5-Aminolevulinate Synthetase; D011163:Hydroxymethylbilane Synthase; D008190:Lyases