Cobalt inhibition of synthesis and induction of delta-aminolevulinate synthase in liver.

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Abstract
Co has complex actions on the metabolism of heme in the [rat] 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 Co 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. Co almost entirely blocked the ability of the barbiturate analog allylisopropylacetamide to induce .delta.-aminolevulinate synthase in liver. The blocking effect of Co 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 h after allylisopropylacetamide, inhibiton of enzyme induction was incomplete. Co 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. The mechanism of early Co inhibition of .delta.-aminolevulinate synthase probably involves direct binding of the ionic metal to a regulatory site for this enzyme. The later increase in .delta.-aminolevulinate synthase formation possibly is due to derepression of enzyme synthesis resulting from depletion of cellular heme content following metal induction of heme oxygenase.

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