Metabolic induction of the hepatic cytochrome P450 system by chlorfenvinphos in rats.
Previous studies have shown that a single oral pretreatment of rats with the organophosphorus insecticide 2-chloro-1-(2,4-dichlorophenyl)vinyl diethyl phosphate (chlorfenvinphos, CVP) afforded protection against the toxicity of a subsequent challenge with the same compound within 24 hr. This protection may be due to the reduction in brain cholinesterase inhibition caused by the decrease in plasma CVP concentration. The purpose of this study was to investigate the mechanism of the decrease in plasma CVP concentration in relation to metabolic induction. CVP was preferentially metabolized by a liver microsomal fraction with an NADPH-generating system, compared with serum or kidney subcellular fractions. A single oral 24-hr pretreatment with CVP (15 mg/kg) increased the oral LD50 of its next dosage to threefold. The same treatment also increased CVP metabolism (to 178%), cytochrome P450 content (to 130%), cytochrome P450 reductase activity (to 130%), cytochrome b5 content (to 121%), and cytochrome P450-linked activities such as aminopyrine demethylase (to 140%) and aniline hydroxylase (to 127%) in the hepatic microsomal fraction. A single oral 24-hr pretreatment of phenobarbital (50 mg/kg), which is known as an inducer of cytochrome P450, increased the oral LD50 of CVP and all the related metabolic parameters listed above in an order of magnitude similar to that of CVP, although the increments induced by the phenobarbital treatment were greater than those induced by the CVP treatment. These results indicate that the increase in hepatic CVP metabolism may be due to the induction of the hepatic cytochrome P450 system caused by the single oral short-term treatment with CVP. This induction may be one of the reasons for the decrease in plasma CVP concentration which may be responsible for the reduction in toxicity of its next dosage.
Ikeda
T
T
Mitsukaido Laboratories, Institute of Environmental Toxicology, Ibaraki, Japan.
Tsuda
S
S
Shirasu
Y
Y
D000818:Animals; D002709:Chlorfenvinphos / Q000378:metabolism / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D015786:Cytochromes b5 / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D006591:Hexobarbital / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010243:Paralysis / Q000139:chemically induced; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012890:Sleep / Q000187:drug effects; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology; D015049:Zoxazolamine
D011506:Proteins; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D015049:Zoxazolamine; D006591:Hexobarbital; D009251:NADPH-Ferrihemoprotein Reductase; D002709:Chlorfenvinphos