Roles of nitric oxide in inflammatory downregulation of human cytochromes P450.

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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

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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	Unknown	Inhibitor	Details

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