Cobalt induction of hepatic heme oxygenase; with evidence that cytochrome P-450 is not essential for this enzyme activity.
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.
D000818:Animals; D001663:Bilirubin / Q000096:biosynthesis; D003035:Cobalt / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction; D006418:Heme; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009022:Morphine Derivatives / Q000378:metabolism; D051381:Rats; D014508:Urea / Q000494:pharmacology
D009022:Morphine Derivatives; D003035:Cobalt; D006418:Heme; D014508:Urea; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001663:Bilirubin