Inhibitory effect of zinc-protoporphyrin on the induction of heme oxygenase and the associated decrease in cytochrome P-450 content in rats.
Pretreatment of rats with zinc-protoporphyrin, which has shown to be a potent competitive inhibitor of heme oxygenase, resulted in the inhibition of bromobenzene-mediated induction of heme oxygenase and decreases of the cytochrome P-450 content, aminopyrine demethylase and aniline hydroxylase activities. Such an inhibitory effect of zinc-protoporphyrin on the induction of heme oxygenase and concomitant decreases of drug-metabolizing enzymes occurred in a dose-dependent manner with complete inhibition of these effects at a dose of 40 mumol/kg. The effects of zinc-protoporphyrin were also observed in thioacetamide- and BCG-treated rats and ascitic tumor AH 66-bearing rats. Likewise, a decrease of cytochrome b5 content observed under these experimental conditions was also restored significantly by zinc-protoporphyrin. These results strongly suggest that the induction of heme oxygenase is a primarily important early event which consequently leads to the decrease in cytochrome P-450 content and associated enzyme activities.
Matsuura
Y
Y
Department of Hygienic Chemistry, Showa College of Pharmaceutical Sciences, Tokyo, Japan.
Fukuda
T
T
Yoshida
T
T
Kuroiwa
Y
Y
D000633:Aminopyrine N-Demethylase / Q000096:biosynthesis; D000815:Aniline Hydroxylase / Q000096:biosynthesis; D000818:Animals; D001969:Bromobenzenes / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003573:Cytochrome b Group / Q000096:biosynthesis; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D009374:Neoplasms, Experimental / Q000201:enzymology; D011166:Porphyrins / Q000494:pharmacology*; D011524:Protoporphyrins / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013853:Thioacetamide / Q000494:pharmacology
D001969:Bromobenzenes; D003573:Cytochrome b Group; D011166:Porphyrins; D011524:Protoporphyrins; D013853:Thioacetamide; C017803:zinc protoporphyrin; D003577:Cytochrome P-450 Enzyme System; C032036:bromobenzene; D006899:Mixed Function Oxygenases; D000815:Aniline Hydroxylase; D006419:Heme Oxygenase (Decyclizing); D000633:Aminopyrine N-Demethylase