Hepatic glutathione and hepatotoxicity: effects of cytochrome P-450 complexing compounds SKF 525-A, L-alpha acetylmethadol (LAAM), norLAAM, and piperonyl butoxide.
Four compounds forming metabolic intermediate complexes with cytochrome P-450 in vitro were studied for their effects on hepatic glutathione in the mouse. All four compounds depleted glutathione within 1-3 hr after administration. The effect was transient for piperonyl butoxide while lasting at least 24 hr for other compounds. Induction of the mixed-function oxidase system by phenobarbital had no effect on the glutathione-depleting actions of the compounds, but induction with 3-methylcholanthrene abolished the depletion seen with piperonyl butoxide and SKF 525-A. For SKF 525-A, L-alpha-acetylmethadol (LAAM) and norLAAM, the persistent lowering of glutathione was paralleled by elevations in serum glutamic-pyruvic transaminase (SGPT) activity. This depletion of glutathione and subsequent elevations in SGPT were found to be strain and species dependent for SKF 525-A, LAAM and norLAAM. Compounds which complex with cytochrome P-450 in vitro may increase drug toxicities in vivo by mechanisms other than inhibition of oxidative drug metabolism.
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D008691:Methadone / Q000031:analogs & derivatives*; D008692:Methadyl Acetate / Q000031:analogs & derivatives / Q000633:toxicity*; D051379:Mice; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010882:Piperonyl Butoxide / Q000633:toxicity; D011335:Proadifen / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
C020783:paracymethadol; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D006899:Mixed Function Oxygenases; D000410:Alanine Transaminase; D005978:Glutathione; D008692:Methadyl Acetate; D010882:Piperonyl Butoxide; D008691:Methadone