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  • Title: Hepatic glutathione and hepatotoxicity: effects of cytochrome P-450 complexing compounds SKF 525-A, L-alpha acetylmethadol (LAAM), norLAAM, and piperonyl butoxide.
    Author: James RC, Harbison RD.
    Journal: Biochem Pharmacol; 1982 May 15; 31(10):1829-35. PubMed ID: 7104014.
    Abstract:
    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.
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