Methyl ethyl ketone peroxide damage to cytochrome P-450 peroxidase activities.
Some new aspects of damage to cytochrome P-450 peroxidase activities by a toxic peroxide were investigated. Methyl ethyl ketone peroxide (MEKP) damage to cytochrome P-450 and inhibition of cytochrome P-450-mediated peroxidase activities were studied. In vivo, hepatic microsomal NADH- and NADPH-peroxidase activities were induced in rats by phenobarbital and 3-methylcholanthrene. Phenobarbital treatment induced more NADH- and NADPH-peroxidase activity than did 3-methylcholanthrene treatment. In vitro, microsomal cytochrome P-450 from rat liver was more sensitive to damage by MEKP than was this protein from rat kidney. Destruction of cytochrome P-450 hemoprotein and inhibition of its associated peroxidase activities by MEKP increased as a function of time of exposure to the peroxide. The addition of MEKP to microsomes resulted in a progressive increase in spectral absorbance at 433 nm. MEKP was an irreversible inhibitor of NADH- and NADPH-peroxidase, and NADH-peroxidase was more sensitive to damage than was NADPH-peroxidase. At 0 time and low concentration, MEKP was immediately bound to microsomal cytochrome P-450 and it exhibited competitive inhibition of NADH- and NADPH-peroxidase. At high concentration, MEKP was a mixed inhibitor of NADH- and NADPH-peroxidase. This study also showed that MEKP is a substrate for microsomal P-450 peroxidase activities and suggests that these peroxidase activities may play an important role in metabolism of toxic lipophilic organic peroxides that enter the endoplasmic reticulum.
D000818:Animals; D002074:Butanones / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010544:Peroxidases / Q000378:metabolism; D010545:Peroxides / Q000494:pharmacology*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D002074:Butanones; D010545:Peroxides; C011007:methyl ethyl ketone peroxide; D008748:Methylcholanthrene; D010088:Oxidoreductases; D010544:Peroxidases; C021845:NAD+ peroxidase; C045195:NADPH peroxidase; D009251:NADPH-Ferrihemoprotein Reductase; D010634:Phenobarbital