Loss and degradation of enzyme-bound heme induced by cellular nitric oxide synthesis

Abstract

We report here that, like nonheme iron, protein-bound intracellular heme iron is also a target for destruction by endogenously produced nitric oxide (·NO). In isolated rat hepatocytes ·NO synthesis results in substantial (approximately 60%) and comparable loss of catalase and cytochrome P450 as well as total microsomal heme, and decreased heme synthetic (δ- aminolevulinate synthetase and ferrochelatase) and increased degradative (heme oxygenase) enzymatic activities. The effect is reversible, and intact cytochrome P450 apoproteins are still present, as judged by heme reconstitution of isolated microsomes. The effects on δ-aminolevulinate synthetase and heme oxygenase are likely to be secondary to heme liberation, while the effects on ferrochelatase appear to be a direct effect of ·NO, perhaps destruction of its nonheme iron-sulfur center.