Erythromycin A-derived macrolides modify the functional activities of human neutrophils by altering the phospholipase D-phosphatidate phosphohydrolase transduction pathway: L-cladinose is involved both in alterations of neutrophil functions and modulation of this transductional pathway.
All erythromycin A derivatives, irrespective of the size of the lactone ring and the nature of the substituent, inhibit oxidant production by neutrophils and promote their degranulation. We demonstrate in this study that the L-cladinose at position 3 of the lactone ring is a key structure in the modulation of these two neutrophil functions, suggesting that this sugar (alone or combined with a lactone structure) interferes with cell target(s) involved in both oxidant production and exocytosis. Taking roxithromycin as an example of erythromycin A derivatives, we also found that these molecules interfered with the phospholipase D (PLD)-phosphatidate phosphohydrolase pathway in two ways. In nonstimulated neutrophils, roxithromycin and all L-cladinose-bearing molecules activated PLD, as reflected by 1-O-[3H]alkyl-2-acyl-phosphatidyl-ethanol production. In addition, these drugs induced an accumulation of 1-O-[3H]alkyl-2-acyl-phosphatidic acid (PA), but not 1-O-[3H]alkyl-2-acylglycerol. PA accumulation seems to be involved in the induction of exocytosis by macrolides, as the roxithromycin-induced release of granular enzymes was impaired strongly in the presence of ethanol. By contrast, in stimulated neutrophils, roxithromycin inhibited PLD activity and totally impaired 1-O-[3H]alkyl-2-acylglycerol production. The inhibition of diglyceride production by roxithromycin (not its descladinosyl derivative) could explain its inhibitory effect on oxidant production. The relevance of our data to the clinical situation, particularly the anti-inflammatory activity of these drugs, requires further investigation.
Abdelghaffar
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INSERM Unité 294, Centre Hospitalier Universitaire Xavier Bichat, Paris, France.
Vazifeh
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Labro
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D004075:Diglycerides / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D005089:Exocytosis / Q000187:drug effects; D020404:Glycerophospholipids; D006601:Hexoses / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D007399:Interphase / Q000187:drug effects / Q000276:immunology; D007700:Kinetics; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology* / Q000502:physiology; D010711:Phosphatidate Phosphatase / Q000037:antagonists & inhibitors / Q000187:drug effects*; D010712:Phosphatidic Acids / Q000096:biosynthesis / Q000494:pharmacology; D010739:Phospholipase D / Q000037:antagonists & inhibitors / Q000187:drug effects*; D015575:Roxithromycin / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000097:blood
D004075:Diglycerides; D020404:Glycerophospholipids; D006601:Hexoses; D010712:Phosphatidic Acids; C051521:phosphatidylethanol; D013481:Superoxides; D015575:Roxithromycin; C013889:cladinose; D004917:Erythromycin; D010711:Phosphatidate Phosphatase; D010739:Phospholipase D