Selenium regulation of hepatic heme metabolism: induction of delta-aminolevulinate synthase and heme oxygenase.

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Abstract
Se was a novel of regulator of cellular [rat] heme metabolism in that the element induced both the mitochondrial enzyme .delta.-aminolevulinate synthase [succinyl-CoA:glycine C-succinyltransferase (decarboxylating); EC 2.3.1.37] and the microsomal enzyme heme oxygenase [heme, H-donor:oxygen oxidoreductase(.alpha.-methene-oxidizing, hydroxylating); EC 1.14.93.3] in liver. The effect of Se on these enzyme activities was prompt, reaching a maximum within 2 h after a single injection. Other changes in parameters of hepatic heme metabolism occurred after administration of the element. Thirty min after injection the cellular content of heme was significantly increased; this value slightly decreased below control values within 2 h, coinciding with the period of rapid induction of heme oxygenase. At later periods heme content returned to normal values. Se treatment caused only a slight decrease in microsomal cytochrome P-450 content. Drug-metabolizing activity was severely inhibited by higher doses of the element. Unlike other inducers of .delta.-aminolevulinate synthase, which as a rule are also porphyrinogenic agents, Se induction of this enzyme was not accompanied by an increase in the cellular content of porphyrins. When rats were pretreated with Se 90 min before administration of heme, a potent inhibitor of .delta.-aminolevulinate synthase production, the inhibitory effect of heme on formation of this mitochondrial enzyme was completely blocked. Se, at high concentrations in vitro, was inhibitory to .delta.-aminolevulinate synthase activity. Se may not be a direct inducer of heme oxygenase as is the case with trace metals such as Co, but may mediate an increase in heme oxygenase through increased production and cellular availability of free heme, which results from the increased heme synthetic activity of hepatocytes. Subsequently, the increased heme oxygenase activity may in turn be responsible for the lack of increase in the microsomal heme content, thus maintaining heme levels at normal values despite the highly increased activities of both heme oxygenase and .delta.-aminolevulinate synthase. The increase in .delta.-aminolevulinate synthase activity is probably not due to a decreased rate of enzyme degradation or an activation of preformed enzyme, but to increased rate of synthesis of enzyme protein. Although Se in trace amounts was postulated to be involved in microsomal electron transfer process, the data from this study indicate that excess Se can substantially inhibit microsomal drug metabolism.