Roles of nitric oxide in inflammatory downregulation of human cytochromes P450.
Article Details
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Aitken AE, Lee CM, Morgan ET
Roles of nitric oxide in inflammatory downregulation of human cytochromes P450.
Free Radic Biol Med. 2008 Mar 15;44(6):1161-8. doi: 10.1016/j.freeradbiomed.2007.12.010. Epub 2007 Dec 23.
- PubMed ID
- 18206661 [ View in PubMed]
- Abstract
The purpose of this study was to determine the role of nitric oxide (NO) in the downregulation of human cytochrome P450 (CYP) enzymes and mRNAs by an inflammatory stimulus in cultured human hepatocytes. We focused on CYP2B6 because previous studies showed that rat CYP2B proteins undergo an NO-dependent degradation in response to inflammatory stimuli. To ensure high-level expression of CYP2B6, the inducer phenytoin was present at all times. Stimulation of cells with a mixture of tumor necrosis factor-alpha, interleukin-1, and interferon-gamma (ILmix) downregulated CYP2B6 mRNA and protein to 9 and 19% of control levels. The NO donor NOC-18 downregulated CYP2B6 protein to 30% of control, with only a small effect on CYP2B6 mRNA. Nitric oxide synthase inhibitors attenuated the downregulation of CYP2B6 protein but not mRNA by ILmix. These findings demonstrate that the posttranscriptional NO-dependent downregulation of CYP2B enzymes, observed previously in rat hepatocytes, is conserved in human CYP2B6. This mechanism is specific for CYP2B6 among the enzymes tested. No evidence was found for regulation of CYP2E1 mRNA or protein by NO. NOC-18 treatment downregulated CYP3A4 mRNA to 50% of control. However, NOS inhibitors failed to block the effects of ILmix on CYP3A4 expression.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Nitric Oxide Cytochrome P450 2B6 Protein Humans UnknownInhibitorDetails - Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Phenytoin Approved Vet Approved CYP2B6 1555 upregulated Phenytoin results in increased expression of CYP2B6 mRNA 19q13.2 Phenytoin Approved Vet Approved CYP2E1 1571 upregulated Phenytoin results in increased expression of CYP2E1 mRNA 10q26.3 Phenytoin Approved Vet Approved CYP3A4 1576 upregulated Phenytoin results in increased expression of CYP3A4 mRNA 7q22.1