Inhibition of biotransformation by nitric oxide (NO) overproduction and toxic consequences

Toxicology Letters
J StadlerJ Doehmer

Abstract

Hepatic nitric oxide (NO) biosynthesis is induced by local or systemic inflammation. The highly reactive NO radical binds to prosthetic iron groups such as heme or iron-sulfur clusters leading to either activation or inhibition of enzymes such as guanylate cyclase, cyclooxygenase and aconitase. It has been known for years that NO also binds to the heme moiety of cytochrome P450s (CYP) with high affinity. However, it was demonstrated recently that binding of NO to CYPs also inhibits their enzymatic activity. This is true for exogenously applied as well as for endogenously synthesized NO. Suppression of CYP-dependent metabolism, which is a major problem of inflammatory liver diseases, can be significantly reversed by inhibition of NO synthesis in vivo under experimental conditions. We investigated whether these findings are applicable as a novel therapeutic principle in severe inflammatory liver dysfunction.

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Citations

Nov 5, 1997·Journal of Pain and Symptom Management·M Anbar, B M Gratt
Oct 18, 2000·Free Radical Biology & Medicine·J ChandraS Orrenius
Nov 4, 2004·Biomedical Papers of the Medical Faculty of the University Palacký, Olomouc, Czechoslovakia·Radim VrzalZdenek Dvorák
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Jul 15, 1998·Journal of Oral and Maxillofacial Surgery : Official Journal of the American Association of Oral and Maxillofacial Surgeons·M Anbar, B M Gratt

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