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Inhibition of nitric oxide synthase isoforms by porphyrins.
- Source :
-
Archives of biochemistry and biophysics [Arch Biochem Biophys] 1996 Sep 01; Vol. 333 (1), pp. 27-34. - Publication Year :
- 1996
-
Abstract
- Protoporphyrin IX inhibits citrulline formation by all three nitric oxide synthase isoforms in a manner reversible by dilution. Zinc protoporphyrin IX, by contrast, produces a time- and concentration-dependent inactivation of all three nitric oxide synthase isoforms, not reversible by dilution. The inhibition of citrulline formation by protoporphyrin IX occurs with IC50 values of 0.8, 4, and 5 microM for the nNOS, iNOS, and eNOS isoforms, respectively. Inhibition by N-methyl-protoporphyrin IX occurs at IC50 values of 6, 5, and 8 microM for the nNOS, iNOS, and eNOS isoforms, respectively. Inhibition of nitric oxide synthase by protoporphyrin IX is a multisite, positively cooperative inhibition that exhibits a Hill coefficient of 2.3 for the iNOS isoform. Protoporphyrin IX reduces the maximal velocity of citrulline formation for both the iNOS and nNOS isoforms without altering the K(m) for the arginine substrate or the EC50 value for the tetrahydrobiopterin cofactor. Protoporphyrin IX inhibits the arginine-independent NADPH oxidase activity of nNOS with an IC50 value of 1 microM but has no effect on cytochrome c reductase activity at concentrations as high as 30 microM. At concentrations of 10 and 20 microM, protoporphyrin IX inhibits NO formation by cytokine-induced murine RAW 264.7 cells; however, these inhibitions are accompanied by significant cellular cytotoxicity. Coproporphyrins I and III, uroporphyrins I and III, and porphobilinogen, intermediates in the biosynthesis of heme that accumulate in hepatic porphyrias, are ineffective as inhibitors of the nitric oxide synthase isoforms. Since protoporphyrin IX is the immediate biosynthetic precursor of heme that accumulates in hepatic protoporphyria, iron deficiency anemia, and lead poisoning, protoporphyrin IX inhibition of nitric oxide synthase may contribute to the pathophysiology of these conditions.
- Subjects :
- Animals
Arginine metabolism
Cattle
Cell Line
Citrulline biosynthesis
Enzyme Inhibitors chemistry
Humans
In Vitro Techniques
Interferon-gamma pharmacology
Kinetics
Mice
Molecular Structure
NADH Dehydrogenase metabolism
NADPH Oxidases metabolism
Porphyrins chemistry
Porphyrins metabolism
Protoporphyrins pharmacology
Rats
Enzyme Inhibitors pharmacology
Isoenzymes antagonists & inhibitors
Nitric Oxide Synthase antagonists & inhibitors
Porphyrins pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0003-9861
- Volume :
- 333
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Archives of biochemistry and biophysics
- Publication Type :
- Academic Journal
- Accession number :
- 8806750
- Full Text :
- https://doi.org/10.1006/abbi.1996.0360