Codeine-mediated hepatotoxicity in isolated rat hepatocytes.

Administration of codeine to freshly isolated rat hepatocytes resulted in cytotoxicity characterized by a dose- and time-dependent leakage of lactate dehydrogenase (LDH) out of the cells. Codeine also caused a decrease in hepatic reduced sulfhydryl content. Cytochrome P-450 content and NADPH levels were not changed. Induction and inhibition studies of several potential pathways of codeine biotransformation were carried out in order to determine if codeine must be metabolized to a reactive intermediate to elicit these hepatotoxic effects. Codeine hepatotoxicity as measured by LDH release was not changed after induction of cytochrome P-450 by phenobarbital and was decreased after cytochrome P-448 induction by beta-naphthoflavone. However, codeine hepatotoxicity was inhibited when an inhibitor of cytochrome P-450 metabolism, metyrapone, was added. Inhibition of the other major hepatic oxidative enzyme system, flavin adenine dinucleotide (FAD)-containing monooxygenase, increased the cytotoxicity of codeine. Inhibition of alcohol dehydrogenase had no effect on codeine hepatotoxicity. These results indicate that codeine hepatotoxicity is caused by a cytochrome P-450-generated intermediate of codeine, whereas FAD-containing monooxygenase may metabolize codeine to a nontoxic intermediate.