MEDLINE Journals

    Killing of cultured hepatocytes by the mixed-function oxidation of ethoxycoumarin.

    Authors
    Gerson RJ, Serroni A, Gilfor D, et al. 
    Source
    Biochem Pharmacol 1986 Dec 1; 35(23) :4311-9.
    Abstract

    Ethoxycoumarin is metabolized by mixed-function oxidation to give 7-hydroxycoumarin (umbelliferone) and acetaldehyde, without formation of an intermediate electrophile. Ethoxycoumarin was found, nevertheless, to injure cultured rat hepatocytes. Male hepatocytes were more sensitive than female to ethoxycoumarin. Phenobarbital increased cell killing, and SKF 525A, an inhibitor of ethoxycoumarin metabolism, prevented it. Neither umbelliferone nor acetaldehyde were toxic. Cellular glutathione decreased and oxidized glutathione (GSSG) accumulated in the culture medium. Sulfhydryl reagents prevented the cell killing without inhibiting metabolism. Lipid peroxidation was detected prior to evidence of cell death, and the antioxidant N,N'-diphenyl-phenylenediamine prevented both the lipid peroxidation and cell killing without inhibiting metabolism. Inhibition of glutathione reductase with 1,3-bis(chloroethyl)-1-nitrosourea potentiated the cell killing without increasing metabolism. Pretreatment of the cells with the ferric iron chelator deferoxamine reduced cell killing, again without inhibiting metabolism. Ferric chloride restored the sensitivity of deferoxamine-pretreated hepatocytes to ethoxycoumarin. These data define a new experimental model in which lethal liver cell injury is dependent on the metabolism of ethoxycoumarin but unrelated to its two known metabolites. An oxidative stress accompanying the cytochrome P-450-dependent metabolism of ethoxycoumarin is proposed as the mechanism coupling metabolism to lethal cell injury.

    Mesh
    Animals
    Carmustine
    Cell Survival
    Cells, Cultured
    Coumarins
    Deferoxamine
    Glutathione
    Glutathione Reductase
    Iron
    Lipid Peroxides
    Liver
    Oxidation-Reduction
    Phenylenediamines
    Proadifen
    Rats
    Rats, Inbred Strains
    Language

    eng

    Pub Type(s)
    Journal Article Research Support, U.S. Gov't, P.H.S.
    PubMed ID

    3790155

    Content Manager
    Related Content

    Oxidative cell injury in the killing of cultured hepatocytes by allyl alcohol.

    Protein thiol depletion and the killing of cultured hepatocytes by hydrogen peroxide.

    Toxic consequence of the abrupt depletion of glutathione in cultured rat hepatocytes.

    Evidence for the participation of activated oxygen species and the resulting peroxidation of lipids in the killing of cultured hepatocytes by aryl halides.

    Oxygen-mediated cell injury in the killing of cultured hepatocytes by acetaminophen.

    1,3-(2-Chloroethyl)-1-nitrosourea potentiates the toxicity of acetaminophen both in the phenobarbital-induced rat and in hepatocytes cultured from such animals.

    The killing of cultured hepatocytes by N-acetyl-p-benzoquinone imine (NAPQI) as a model of the cytotoxicity of acetaminophen.

    Cellular injury induced by oxidative stress is mediated through lysosomal damage.