Activation of misonidazole by rat liver microsomes and purified NADPH-cytochrome c reductase

McManus, Michael E., Lang, Matti A., Stuart, Karen and Strong, John (1982) Activation of misonidazole by rat liver microsomes and purified NADPH-cytochrome c reductase. Biochemical Pharmacology, 31 4: 547-552.


Author McManus, Michael E.
Lang, Matti A.
Stuart, Karen
Strong, John
Title Activation of misonidazole by rat liver microsomes and purified NADPH-cytochrome c reductase
Formatted title Activation of misonidazole by rat liver microsomes and purified NADPH-cytochrome c reductase
Journal name Biochemical Pharmacology
Publication date 1982-02
Sub-type Article
DOI 10.1016/0006-2952(82)90158-7
Volume number 31
Issue number 4
ISSN 0006-2952; 1873-2968
Start page 547
End page 552
Total pages 6
Place of publication Philadelphia, PA, U.S.A.
Publisher Elsevier
Language eng
Subject C1
1115 Pharmacology and Pharmaceutical Sciences
Formatted abstract Rat liver microsomes and purified NADPH-cytochrome c reductase metabolized [14C]misonidazole anaerobically to a reactive intermediate that covalently binds to tissue macromolecules. Air strongly inhibited the binding whereas carbon monoxide had no effect, indicating that misonidazole is activated via reduction and not by cytochrome P-450-dependent oxidation. Both systems showed an absolute requirement for NADPH and were stimulated by flavine (FAD) and paraquat. The apparent Km for misonidazole binding to microsomal protein was 0.74 mM and the apparent Vmax 0.64 nmole 14C bound · mg−1 · min−1. At a single substrate concentration, nitrofurantoin, nitrofurazone and desmethylmisonidazole inhibited the covalent binding of misonidazole to microsomal protein by 47, 26, and 38% respectively. The effect of nitrofurantoin on the kinetics of misonidazole binding gave a complex interaction indicative of uncompetitive inhibition. Glutathione reduced the binding of misonidazole to microsomal protein below the level observed for boiled microsomes while ascorbic acid had no effect. Compared to nitrofurantoin and paraquat, misonidazole was a poor stimulator of superoxide production as measured by adrenochrome formation.
© Elsevier 1982
Q-Index Code C1

Document type: Journal Article
Sub-type: Article
Collection: National Research Centre for Environmental Toxicology Publications
 
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