Inhibition of murine macrophage nitric oxide synthase expression by a pivoxil prodrug of antiviral acyclic nucleotide analogue 9-(2-phosphonomethoxyethyl)adenine.
The effect of the acyclic nucleotide analogue, 9-(2-phosphonomethoxyethyl)adenine (PMEA, Adefovir), and its (bis)pivaloyloxymethyl ester (bis-POM-PMEA, Adefovir Dipivoxil) on in vitro nitric oxide (NO) production by murine peritoneal macrophages was investigated. Bis-POM-PMEA inhibited in a concentration-dependent manner the formation of NO generated by interferon-gamma and lipopolysaccharide, the IC50 being 15 microM. Suppressed transcription of mRNA for inducible NO synthase (EC 1.14.13.39) resulting in decreased synthesis of NO synthase protein was found. Parent compound PMEA was virtually ineffective.
Zídek
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Z
Institute of Pharmacology, Academy of Sciences of the Czech Republic, Prague. zidekz@biomed.cas.cz
Franková
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Holý
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Boubelík
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M
Dráber
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P
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D011355:Prodrugs / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics
D000998:Antiviral Agents; D008070:Lipopolysaccharides; D011355:Prodrugs; D012333:RNA, Messenger; C089823:bis(pivaloyloxymethyl)-9-(2-phosphonylmethoxyethyl)adenine; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D000225:Adenine