Inhibition of cytochromes P4501A by nitric oxide
| Autor: | J R Siewert, Johannes Doehmer, T. Brill, W. A. Schmalix, J. Trockfeld, H Greim, J. Stadler |
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| Rok vydání: | 1994 |
| Předmět: |
Hamster
CHO Cells Nitric Oxide Chinese hamster Nitric oxide chemistry.chemical_compound Cricetinae Benzo(a)pyrene Cytochrome P-450 CYP1A1 medicine Animals Cytochrome P-450 Enzyme Inhibitors Humans heterocyclic compounds Heme chemistry.chemical_classification Multidisciplinary biology Chinese hamster ovary cell Cytochrome P450 respiratory system biology.organism_classification Rats Enzyme Liver chemistry Biochemistry biology.protein Aryl Hydrocarbon Hydroxylases Sodium nitroprusside Oxidoreductases Research Article medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences. 91:3559-3563 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.91.9.3559 |
| Popis: | Inflammatory stimulation of the liver leads to the induction of nitric oxide (NO) biosynthesis. Because NO binds to the catalytic heme moiety of cytochromes P450 (CYPs), we investigated whether NO interferes with specific CYP-dependent metabolic pathways. In a first experimental approach V79 Chinese hamster cells genetically engineered for stable expression of rat and human CYP1A1 and -1A2 were used. Incubation with the NO donors sodium nitroprusside and S-nitrosylacetylpenicillamine led to a concentration-dependent inhibition of all four CYP enzymes. CYP1A1 was more sensitive to the inhibitory effect of NO than CYP1A2. In the second part of the study, endogenous NO synthesis was induced in rat hepatocytes by incubation with a mixture of cytokines and endotoxin. Concurrently, as NO production in hepatocytes increased within 24 hr, a decrease in CYP1A1-dependent benzo[a]pyrene turnover was observed to almost undetectable levels. The competitive inhibitor of NO synthesis, NG-monomethyl-L-arginine, was able to significantly restore CYP1A1 activity in the presence of cytokines and endotoxin. Inhibition of hepatocellular CYP activity by NO was predominantly due to a direct effect on the enzymes. However, NO-dependent inhibition of CYP expression at a transcriptional level was also demonstrated. Our results indicate that inhibition of NO biosynthesis in patients suffering from systemic inflammatory response syndromes may help to restore biotransformation capacity of the liver. |
| Databáze: | OpenAIRE |
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