Cobalt Induction of Hepatic Heme Oxygenase; with Evidence That Cytochrome P -450 Is Not Essential for This Enzyme Activity

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Abstract
Treatment of rats in vivo with cobalt chloride stimulated heme oxidation by hepatic microsomes to levels up to 800% above controls. This treatment also caused increases in liver weight and in total microsomal protein; in contrast, marked decreases were produced in microsomal oxidation of ethylmorphine (80%), and in cytochrome P -450 (60-70%) and heme (30-50%) contents. Cobalt chloride treatment did not affect heme oxidation by the spleen heme oxygenase system. The rate of heme oxidation by hepatic microsomal enzymes and the microsomal content of cytochrome P -450 were found to be unrelated. This conclusion was reached from studies in which microsomal heme oxygenase activity from cobalt-treated animals could be increased by 900% above control levels in the same microsomal preparation in which cytochrome P -450 content was decreased to spectrally unmeasurable amounts after incubation with 4 M urea. The same treatment eliminated ehtylmorphine demethylation and decreased microsomal NADPH-cytochrome c reductase (EC 1.6.2.4) activity by 75%. It is concluded that ( i ) the hepatic microsomal enzyme system that oxidizes heme compounds is not the same as that which metabolizes drugs, ( ii ) cytochrome P -450 is not essential for the oxidation of heme by liver cells, ( iii ) there is no direct relationship between the rate of heme oxidation and the level of NADPH-cytochrome c reductase activity, and ( iv ) the oxidation of heme is protein-dependent and the active proteins are inducible, but are different from those involved in drug metabolism.