Ability of unstimulated and phorbol-ester-stimulated human blood-monocyte-derived macrophages to metabolize drugs and its implications.
Solutions containing 5,5-diphenyl[4-14C]hydantoin (15 micrograms/ml) or pheno[2-14C]barbital (20 micrograms/ml) were incubated for 0.5-6 h with monolayers of unstimulated and phorbol-ester-stimulated human blood-monocyte-derived macrophages and suspensions of K562 cells. The incubated solutions were centrifuged and the cell-free supernatants subjected to chromatography on Q-Sepharose Fast Flow anion exchange resin. The interaction with unstimulated macrophages but not with K562 cells resulted in a time-dependent conversion of the original radioactive drug molecules to molecules with a larger negative charge in the case of diphenylhydantoin and a smaller negative charge in the case of phenobarbital. These conversions were prevented by 20 mM tetrahydrofurane and partially inhibited by 300 U/ml superoxide dismutase (SOD) and, therefore, appeared to depend on cytochrome-P-450-mediated reactions and to some extent also on superoxide anion radicals. Macrophages which were stimulated by 20 nM phorbol myristate acetate metabolized both drugs at much faster rates than unstimulated macrophages. Since this increased metabolism was abolished in the presence of SOD, it appeared to be entirely dependent on superoxide anion radicals. These data provide biochemical evidence that unstimulated human monocyte-derived macrophages have a substantial capacity to metabolize certain xenobiotics and that stimulated macrophages have an even greater capacity to do so. This property of macrophages may have considerable biological significance and be important in the pathogenesis both of drug-induced tissue damage and of malignant disease.
Wickramasinghe
S N
SN
Department of Haematology, St, Mary's Hospital Medical School, Imperial College of Science, Technology & Medicine, University of London, UK.
Barden
G
G
Gardner
B
B
D002852:Chromatography, Ion Exchange; D005663:Furans / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology; D010634:Phenobarbital / Q000378:metabolism; D010672:Phenytoin / Q000378:metabolism; D012997:Solvents / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D005663:Furans; D012997:Solvents; C018674:tetrahydrofuran; D010672:Phenytoin; D013482:Superoxide Dismutase; D013755:Tetradecanoylphorbol Acetate; D010634:Phenobarbital