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Toxicological implications of the mixed-function oxidase catalyzed metabolism of carbon disulfide

R R Dalvi, A L HUNTER, R A Neal

    Chemico-Biological Interactions
    |May 1, 1975
    PubMed

    Insights

    Carbon disulfide (CS2) metabolism by hepatic enzymes releases sulfur atoms that bind to microsomes, inhibiting enzyme activity and reducing cytochrome P-450. This mechanism explains CS2-induced liver damage and enzyme system dysfunction.

    Area of Science:

    • Biochemistry
    • Toxicology
    • Enzymology

    Background:

    • Hepatic mixed-function oxidase (MFO) systems are crucial for metabolizing xenobiotics.
    • Cytochrome P-450 (CYP450) is a key enzyme in MFO systems, involved in detoxification and metabolism.
    • Carbon disulfide (CS2) is a known hepatotoxin, but its precise mechanism of toxicity is not fully elucidated.

    Purpose of the Study:

    • To elucidate the mechanism by which carbon disulfide (CS2) inhibits hepatic microsomal enzymes.
    • To investigate the role of sulfur atom release in CS2-induced toxicity.
    • To determine the impact of CS2 metabolism on cytochrome P-450 concentration and activity.

    Main Methods:

    • Incubation of rat liver microsomes with CS2 and NADPH.
    • Measurement of MFO enzyme activity and CYP450 concentration.
    • Analysis of metabolites, including carbonyl sulfide (COS).
    • In vivo administration of CS2 to phenobarbital-pretreated rats.

    Main Results:

    • CS2 metabolism by MFO releases sulfur, which binds to microsomes, inhibiting benzphetamine metabolism and decreasing CYP450.
    • Carbonyl sulfide (COS), a metabolite of CS2, is further metabolized, releasing sulfur that also binds to microsomes.
    • In vivo CS2 administration to rats leads to decreased CYP450 and liver damage, attributed to the binding of released sulfur atoms.
    • CS2 incubation does not cause heme destruction or dissociation from apoenzyme, as total protoheme levels remain unchanged.

    Conclusions:

    • The inhibitory effects of CS2 on hepatic MFO and CYP450 are primarily due to the binding of released sulfur atoms to microsomal proteins.
    • CS2 toxicity involves a cascade of sulfur release and binding, affecting critical metabolic enzymes.
    • The observed liver damage in vivo is a consequence of this sulfur-binding mechanism, not heme degradation.

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