Hepatic glutathione and hepatotoxicity: effects of cytochrome P-450 complexing compounds SKF 525-A, L-alpha acetylmethadol (LAAM), norLAAM, and piperonyl butoxide

Biochem Pharmacol. 1982 May 15;31(10):1829-35. doi: 10.1016/0006-2952(82)90484-1.


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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alanine Transaminase / metabolism
  • Animals
  • Cricetinae
  • Cytochrome P-450 Enzyme System / metabolism*
  • Glutathione / metabolism*
  • Liver / drug effects*
  • Liver / metabolism
  • Male
  • Mesocricetus
  • Methadone / analogs & derivatives*
  • Methadyl Acetate / analogs & derivatives
  • Methadyl Acetate / toxicity*
  • Mice
  • Mixed Function Oxygenases / metabolism
  • Piperonyl Butoxide / toxicity
  • Proadifen / toxicity*
  • Rats
  • Rats, Inbred Strains


  • paracymethadol
  • Cytochrome P-450 Enzyme System
  • Proadifen
  • Mixed Function Oxygenases
  • Alanine Transaminase
  • Glutathione
  • Methadyl Acetate
  • Piperonyl Butoxide
  • Methadone