Generation of free radical intermediates from foreign compounds by neutrophil-derived oxidants.
A large number of foreign compounds, including many drugs, industrial pollutants, and environmental chemicals, can be oxidized under appropriate conditions to potentially toxic free radical intermediates. We evaluated the ability of the oxidants produced by the neutrophil myeloperoxidase system to generate free radical intermediates from several such compounds. Sodium hypochlorite or hypochlorous acid produced by human peripheral blood neutrophils and trapped in the form of taurine chloramine were both found to be capable of producing free radicals from chlorpromazine, aminopyrine, and phenylhydrazine. These radical intermediates were demonstrated by visible light spectroscopy and by direct electron spin resonance (for the chlorpromazine and aminopyrine radicals) or by spin-trapping (for the phenyl radical generated from phenylhydrazine). Stable oxidants produced by the neutrophils (i.e., those present in the supernatants of stimulated neutrophils in the absence of added taurine) also were found to be capable of generating free radical intermediates. The production of the oxidants and the ability of neutrophil supernatants to generate these radicals were almost completely eliminated by sodium azide, a myeloperoxidase inhibitor. We suggest that the oxidation by neutrophils of certain chemical compounds to potentially damaging electrophilic free radical forms may represent a new metabolic pathway for these substances and could be important in the processes of drug toxicity and chemical carcinogenesis.
Kalyanaraman
B
B
Sohnle
P G
PG
D000632:Aminopyrine / Q000378:metabolism; D002700:Chloramines / Q000502:physiology*; D002746:Chlorpromazine / Q000378:metabolism; D005609:Free Radicals; D006801:Humans; D006997:Hypochlorous Acid / Q000502:physiology*; D066298:In Vitro Techniques; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D010659:Phenylhydrazines / Q000378:metabolism; D012973:Sodium Hypochlorite / Q000494:pharmacology; D013654:Taurine / Q000494:pharmacology
D002700:Chloramines; D005609:Free Radicals; D010659:Phenylhydrazines; D000632:Aminopyrine; C030299:phenylhydrazine; D013654:Taurine; D006997:Hypochlorous Acid; D012973:Sodium Hypochlorite; D002746:Chlorpromazine