Inhibition of neutrophil superoxide secretion by the preservative, methylhydroxybenzoate: effects mediated by perturbation of intracellular Ca2+?
The preservative, methylhydroxybenzoate inhibited O2- secretion from human neutrophils activated by both the chemotactic peptide fMet-Leu-Phe and phorbol myristate acetate (PMA): the low level of oxidant secretion activated by the ionophore A23187 was similarly reduced in preservative-treated suspensions. Oxidant secretion was similarly reduced in fMet-Leu-Phe and A23187 treated suspensions in which intracellular Ca2+ was buffered by loading with Quin-2, indicating that methylhydroxybenzoate may exert its effects by perturbation of intracellular Ca2(+)-dependent processes. Methylhydroxybenzoate could mimic EGTA in preventing the Ca2+ dependent enhancement of trypsin activity and could also bind this cation in experiments using a Ca2+ electrode, although the preservative bound Ca2+ more slowly and had a lower affinity than EGTA. These data indicate that methylhydroxybenzoate may exert its effects on neutrophils by perturbation of Ca2(+)-dependent activation pathways and this phenomenon may also explain its other known pharmacological effects. Furthermore, these observations provide an insight into the mechanisms by which intracellular Ca2+ may regulate oxidant secretion.
Edwards
S W
SW
Department of Biochemistry, University of Liverpool.
Humphreys
J M
JM
Taylor
C D
CD
Soulioti
A M
AM
Brunton
A H
AH
Gadd
G M
GM
Hart
C A
CA
D002118:Calcium / Q000378:metabolism; D002614:Chelating Agents; D004533:Egtazic Acid / Q000494:pharmacology; D005609:Free Radicals; D006801:Humans; D066298:In Vitro Techniques; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010226:Parabens / Q000494:pharmacology*; D011310:Preservatives, Pharmaceutical / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014357:Trypsin / Q000378:metabolism
D002614:Chelating Agents; D005609:Free Radicals; D010226:Parabens; D011310:Preservatives, Pharmaceutical; D013481:Superoxides; D004533:Egtazic Acid; D009240:N-Formylmethionine Leucyl-Phenylalanine; C015358:methylparaben; D014357:Trypsin; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium