Evidence of drug metabolism by macrophages: possible role of macrophages in the pathogenesis of drug-induced tissue damage and in the activation of environmental procarcinogens.
After interaction with human macrophages derived from blood, bone marrow or spleen, solutions of sodium phenobarbitone, phenytoin sodium and chlorpromazine hydrochloride showed reduced cytotoxicity towards K562 cells. The reduction in cytotoxicity was partially suppressed in the presence of tetrahydrofurane, an inhibitor of cytochrome P450. These data suggest that macrophages are capable of metabolizing certain drugs, probably via a cytochrome P450-dependent mechanism. The present findings raise the possibility that some drug-induced blood dyscrasias are caused by metabolism of the drug by bone marrow macrophages and the consequent release of relatively short-lived molecules which are toxic to adjacent haemopoietic cells. The generation of cytotoxic molecules during drug metabolism by macrophages may also be responsible for drug-induced damage to other macrophage-rich tissues. In addition, since cytochrome P450-dependent reactions seem to occur within macrophages, these cells may activate environmental procarcinogens and thus plays a role in carcinogenesis and leukaemogenesis.
D002477:Cells / Q000187:drug effects*; D002478:Cells, Cultured; D002746:Chlorpromazine / Q000378:metabolism / Q000633:toxicity; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005663:Furans / Q000494:pharmacology; D006801:Humans; D008658:Inactivation, Metabolic; D008264:Macrophages / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010634:Phenobarbital / Q000378:metabolism / Q000633:toxicity; D010672:Phenytoin / Q000378:metabolism / Q000633:toxicity; D013936:Thymidine / Q000378:metabolism
D005663:Furans; D004364:Pharmaceutical Preparations; C018674:tetrahydrofuran; D010672:Phenytoin; D003577:Cytochrome P-450 Enzyme System; D002746:Chlorpromazine; D013936:Thymidine; D010634:Phenobarbital