Induction of cytochromes P450IIE1 and P450IIB1 by secondary ketones and the role of P450IIE1 in chloroform metabolism.
It has been shown previously that the potentiation of chloroform-induced hepatotoxicity by linear secondary ketones increases with the carbon-chain length. The present work examines the possibility that this potentiation is due to the induction of P450IIE1. The metabolism of chloroform, as measured using headspace gas chromatography, in the presence of microsomes from acetone-treated rats was elevated threefold compared to controls. Inclusion of monoclonal antibody against P450IIE1 inhibited the metabolism by 81%. Alternate substrates of P450IIE1 were also inhibitory. Chloroform metabolism was observed using purified, reconstituted P450IIE1 plus cytochrome b5, but was not detected using P450IIB1. The inductive effect of 18-hr oral pretreatment (15 mmol/kg body wt) with each of three secondary ketones on two isozymes of rat liver microsomal cytochrome P450, P450IIE1, and P450IIB1 was studied. The content of total microsomal P450 and NADPH-dependent cytochrome c reductase, the rates of oxidation of N-nitrosodimethylamine, benzphetamine, and pentoxyresorufin, as well as levels of immunoreactive protein for both of the isozymes were elevated by the pretreatments in the rank order of acetone less than or equal to 2-butanone less than 2-hexanone, in agreement with other trends noted by previous investigators. The results provide further evidence for the role of P450IIE1 induction in the potentiation phenomenon.
Brady
J F
JF
Department of Chemical Biology and Pharmacognosy, College of Pharmacy, Rutgers University, Piscataway, New Jersey 08855.
Li
D
D
Ishizaki
H
H
Lee
M
M
Ning
S M
SM
Xiao
F
F
Yang
C S
CS
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D002725:Chloroform / Q000378:metabolism / Q000633:toxicity*; D002849:Chromatography, Gas; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007659:Ketones / Q000633:toxicity*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D007659:Ketones; D002725:Chloroform; D003577:Cytochrome P-450 Enzyme System