Evidence for the catabolism of polychlorinated biphenyl-induced cytochrome P-448 by microsomal heme oxygenase, and the inhibition of delta-aminolevulinate dehydratase by polychlorinated biphenyls.
Polychlorinated biphenyls (PCB) are potent inducers of hepatic microsomal CO-binding hemoprotein P-448 (P1-450) and of delta-aminolevulinate synthetase (ALAS) activity. Inorganic cobalt was able to block PCB induction of cytochrome P-448 and to modify the PCB effect on ALAS activity in a time-dependent manner. PCB were also found to decrease the activity of delta-aminolevulinic acid dehydratase (ALAD) in liver. Pretreatment of rats with cobalt (30 min) produced the following changes in PCB actions on heme metabolism in liver: (a) augmentation of the porphyrinogenic effect of PCB, as determined by the total porphyrin content and ALAS activity; (b) augmentation of PCB inhibition of ALAD activity; and (c) blockade of induction of microsomal hemoprotein (cytochrome P-448). PCB did not interfere with cobalt induction of hepatic heme oxygenase activity. The sequence of administration of the metal and the PCB was important in relation to the changes produced in hepatic ALAS activity and microsomal hemoprotein and heme contents. When cobalt was administered 24 h after PCB treatment, the magnitude of induction of ALAS by PCB was lowered, and there was a great reduction in microsomal hemoprotein and heme contents. The renal response to PCB was different than that of the liver. In the kidney, PCB blocked the induction of heme oxygenase and depletion of cellular heme produced by cobalt. Furthermore, renal microsomal heme content was increased by PCB treatment alone or in combination with cobalt. It is concluded that (a) the heme moiety of microsomal cytochrome P-448 is metabolized by the heme oxygenase system, and it is suggested that for this catabolism to take place, the hemoprotein must be first converted to the denatured form of the hemoprotein, cytochrome P-420; (b) that the synthesis of heme in the kidney and the liver are regulated through different mechanisms; and (c) that ionic cobalt controls activity of ALAS by first inhibiting synthesis of the enzyme followed by the indirect induction of the enzyme as a result of the catabolism of heme, the physiological repressor of ALAS, by the metal-induced heme oxygenase. Thus microsomal heme oxygenase may be viewed as having an overall regulatory role in relation to mictochondrial ALAS by virtue of its ability to catabolize endogenous heme.
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000818:Animals; D003035:Cobalt / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003580:Cytochromes / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D005037:Ethylmorphine-N-Demethylase / Q000378:metabolism; D006418:Heme / Q000378:metabolism; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D000623:Porphobilinogen Synthase / Q000037:antagonists & inhibitors*; D011166:Porphyrins / Q000378:metabolism; D051381:Rats
D003580:Cytochromes; D011166:Porphyrins; D003035:Cobalt; D006418:Heme; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D006899:Mixed Function Oxygenases; D005037:Ethylmorphine-N-Demethylase; D000624:5-Aminolevulinate Synthetase; D006836:Hydro-Lyases; D000623:Porphobilinogen Synthase