Selective inhibition by phenytoin of chemotactic factor - stimulated neutrophil functions.
We have found that pretreatment of human neutrophils with phenytoin (0.05 to 0.8 mM) results in concentration-dependent, reversible inhibition of both superoxide anion generation and release of lysosomal enzymes (myeloperoxidase, lysozyme, beta-glucuronidase) provoked by either the synthetic peptide, N-formyl-methionyl-leucyl-phenylalanine (FMLP) or the complement fragment C5a. In contrast, phenytoin did not inhibit either enzyme release or superoxide anion generation by neutrophils stimulated with phorbol myristate acetate or serum-opsonized zymosan particles. Phenytoin did not provoke leakage from neutrophils of the cytoplasmic enzyme, lactate dehydrogenase, and did not inhibit directed migration (chemotaxis) of neutrophils toward either FMLP or C5a. Specific binding of 3H-FMLP to neutrophil membrane receptors was not altered significantly by pretreatment of the cells with a wide range of concentrations of phenytoin. With flow microfluorometry and the fluorochrome, 3,3'-dipentyloxacarbocyanine, phenytoin was shown to prevent FMLP-induced changes in fluorescence intensity (i.e., apparent neutrophil membrane depolarization). These data indicate that various neutrophil functions may be regulated independently at other than the receptor level and that neutrophil chemotactic responses to FMLP and C5a do not appear to be dependent on membrane events registered by 3,3'-dipentyloxacarbocyanine.
D000818:Animals; D002630:Chemotactic Factors / Q000037:antagonists & inhibitors*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003182:Complement C5 / Q000378:metabolism; D015936:Complement C5a; D004305:Dose-Response Relationship, Drug; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009113:Muramidase / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D010672:Phenytoin / Q000494:pharmacology*; D012756:Sheep; D013481:Superoxides / Q000378:metabolism
D002630:Chemotactic Factors; D003182:Complement C5; D013481:Superoxides; D009240:N-Formylmethionine Leucyl-Phenylalanine; D010672:Phenytoin; D015936:Complement C5a; D007770:L-Lactate Dehydrogenase; D009195:Peroxidase; D009113:Muramidase; D005966:Glucuronidase