Inhibition of the induction of nitric oxide synthase by spermine is modulated by aldehyde dehydrogenase.
The observation that spermine inhibits the endotoxin (lipopolysaccharide; LPS) induced production of nitric oxide (NO) in macrophages has been ascribed to the conversion of SP to active metabolites by the action of enzymes, such as diamine oxidases, found, for example, in bovine sera. Inhibitory effect is also observed with the oxidised metabolite of spermine, spermine dialdehyde (SDA). Inhibition appears to be at the level of induction of the inducible isoform of NO synthase (iNOS). Here we show that the activity of endogenous aldehyde dehydrogenase present in the cells influences the degree of inhibition seen with either spermine or SDA. Most significantly, inhibition of aldehyde dehydrogenase activity greatly increases (100 fold) the ability of spermine to inhibit the production of nitrite by LPS- induced macrophages. This is presumably by preserving aldehyde metabolites of spermine and thus increasing its action on the induction of iNOS. Thus, inhibition of aldehyde dehydrogenase activity in vitro or in vivo may be a useful approach to enhance the inhibitory effect of polyamines or polyamine aldehydes on iNOS induction.
Southan
G J
GJ
William Harvey Research Institute, St. Bartholomew's Hospital Medical College, London, United Kingdom.
Szabó
C
C
Thiemermann
C
C
D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019001:Nitric Oxide Synthase; D009573:Nitrites / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology*; D010128:p-Aminoazobenzene / Q000031:analogs & derivatives / Q000494:pharmacology
D008070:Lipopolysaccharides; D009573:Nitrites; C007368:C.I. Solvent Yellow 56; C050864:N,N'-bis(3-propionaldehyde)-1,4-diaminobutane; D013096:Spermine; D010128:p-Aminoazobenzene; D019001:Nitric Oxide Synthase; D000444:Aldehyde Dehydrogenase; D000594:Amino Acid Oxidoreductases