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Related Experiment Videos

Codeine-mediated hepatotoxicity in isolated rat hepatocytes.

S P Ellington, G M Rosen

    Toxicology and Applied Pharmacology
    |August 1, 1987
    PubMed
    Summary

    Codeine causes liver cell damage (cytotoxicity) by releasing lactate dehydrogenase (LDH). A cytochrome P-450 enzyme generates a toxic intermediate, while another enzyme may detoxify codeine.

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    Area of Science:

    • Hepatotoxicity
    • Drug Metabolism
    • Biochemistry

    Background:

    • Codeine is an opioid analgesic with known toxic effects.
    • Understanding codeine's metabolic pathways is crucial for assessing its safety.
    • Hepatotoxicity is a significant concern for drug safety evaluations.

    Purpose of the Study:

    • To investigate the mechanisms underlying codeine-induced hepatotoxicity in rat hepatocytes.
    • To determine the role of specific metabolic enzymes in codeine's toxic effects.
    • To identify whether codeine requires metabolic activation to exert its cytotoxic effects.

    Main Methods:

    • Primary rat hepatocytes were used to assess codeine's cytotoxicity.
    • Lactate dehydrogenase (LDH) release was measured as an indicator of cell damage.
    • Enzyme induction and inhibition studies were performed using various agents targeting cytochrome P-450, FAD-containing monooxygenase, and alcohol dehydrogenase.

    Main Results:

    • Codeine induced dose- and time-dependent cytotoxicity, evidenced by LDH leakage and decreased reduced sulfhydryl content.
    • Cytochrome P-450 metabolism generated a hepatotoxic intermediate, as indicated by inhibition with metyrapone.
    • Flavin adenine dinucleotide (FAD)-containing monooxygenase inhibition enhanced codeine cytotoxicity, suggesting its role in detoxification.

    Conclusions:

    • Codeine hepatotoxicity is mediated by a cytochrome P-450-generated reactive intermediate.
    • Flavin adenine dinucleotide (FAD)-containing monooxygenase may play a protective role by metabolizing codeine into a non-toxic compound.
    • These findings highlight the importance of specific metabolic pathways in determining drug-induced liver injury.

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