Roles of nitric oxide in inflammatory downregulation of human cytochromes P450

Aitken, Alison E.; Lee, Choon‐Myung; Morgan, Edward T.

doi:10.1016/j.freeradbiomed.2007.12.010

Cited by 48 publications

(49 citation statements)

References 44 publications

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“…CYP3A4 mRNA is down-regulated by proinflammatory cytokine treatments in primary human hepatocytes (Aitken and Morgan, 2007;Aitken et al, 2008), but neither its mRNA nor protein down-regulation is NO-dependent. The NO-responsiveness of human CYP3A5 and CYP3A7 remains to be determined.…”

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confidence: 94%

Dual Mechanisms of CYP3A Protein Regulation by Proinflammatory Cytokine Stimulation in Primary Hepatocyte Cultures

Lee¹,

Pohl²,

Morgan³

2009

Drug Metab Dispos

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ABSTRACT:Whereas many cytochrome P450 enzymes are transcriptionally suppressed by inflammatory stimuli, down-regulation of CYP2B protein by the inflammatory cytokine interleukin (IL)-1␤ is nitric oxide (NO)-dependent and occurs via polyubiquitination and proteasomal degradation. Here, we used iTRAQ proteomic analysis to search for other proteins that are potentially down-regulated by cellular NO in cultured rat hepatocytes, and we identified CYP3A1 as one such protein. Therefore, we examined whether CYP3A proteins, like CYP2B, undergo NO-and proteasome-dependent degradation in response to cytokine treatment of rat hepatocytes. In cultured rat hepatocytes treated with phenobarbital, IL-1␤ stimulation failed to down-regulate CYP3A1 mRNA within 24 h of treatment, whereas CYP3A protein was down-regulated to 40% of control within 6 h, showing the post-transcriptional down-regulation of CYP3A1 protein.

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confidence: 94%

Dual Mechanisms of CYP3A Protein Regulation by Proinflammatory Cytokine Stimulation in Primary Hepatocyte Cultures

Lee¹,

Pohl²,

Morgan³

2009

Drug Metab Dispos

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“…The role of higher NO levels in causing a feedback loop triggering anti-inflammatory mechanisms can be a potential therapeutic approach in NASH, given the use of an NO donor in a single study for NASH remediation involving ob/ob mice, the spontaneous knockout (KO) of leptin, where no mechanistic inputs were provided (de Oliveira et al, 2008). Along with studies of the boosting of NO levels are the extensive studies about the role of NO in inhibiting CYP2E1; the use of an NO donor to treat NASH can be an excellent regimen (Gergel et al, 1997;Aitken et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

M1 Polarization Bias and Subsequent Nonalcoholic Steatohepatitis Progression Is Attenuated by Nitric Oxide Donor DETA NONOate via Inhibition of CYP2E1-Induced Oxidative Stress in Obese Mice

Seth

Das

Pourhoseini

et al. 2014

J Pharmacol Exp Ther

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Activation of M1 macrophages in nonalcoholic steatohepatitis (NASH) is produced by several external or endogenous factors: inflammatory stimuli, oxidative stress, and cytokines are known. However, any direct role of oxidative stress in causing M1 polarization in NASH has been unclear. We hypothesized that CYP2E1-mediated oxidative stress causes M1 polarization in experimental NASH, and that nitric oxide (NO) donor administration inhibits CYP2E1-mediated inflammation with concomitant attenuation of M1 polarization. Because CYP2E1 takes center stage in these studies, we used a toxin model of NASH that uses a ligand and a substrate of CYP2E1 for inducing NASH. Subsequently, we used a methionine and choline-deficient diet-induced rodent NASH model where the role of CYP2E1 in disease progression has been shown. Our results show that CYP2E1 causes M1 polarization bias, which includes a significant increase in interleukin-1b (IL-1b) and IL-12 in both models of NASH, whereas CYP2E1-null mice or diallyl sulfide administration prevented it. Administration of gadolinium chloride (GdCl 3 ), a macrophage toxin, attenuated both the initial M1 response and the subsequent M2 response, showing that the observed increase in cytokine levels is primarily from macrophages. Based on the evidence of an adaptive NO increase, the NO donor administration in vivo that mechanistically inhibited CYP2E1 catalyzed the oxidative stress during the entire study in NASHabrogated M1 polarization and NASH progression. The results obtained show the association of CYP2E1 in M1 polarization, and that inhibition of CYP2E1 catalyzed oxidative stress by an NO donor (DETA NONOate [(Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) amino]diazen-1-ium-1,2-diolate]) can be a promising therapeutic strategy in NASH.

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“…We showed previously that, similar to rat CYP2B1, human CYP2B6 protein undergoes NO-dependent downregulation in human hepatocytes (Aitken et al, 2008). In addition to CYP2C22, Qian et al (2010) showed the related human CYP2C9 mRNA to be regulated by atRA.…”

Section: Discussionmentioning

confidence: 78%

“…We have shown that NO produced by interleukin-1 (IL-1)b or lipopolysaccharide stimulation of hepatocytes causes ubiquitin-dependent proteasomal degradation of the rat phenobarbital-inducible P450 CYP2B1 (Ferrari et al, 2001;Lee et al, 2008;Sun et al, 2012). The related human enzyme CYP2B6 also undergoes downregulation at the protein level in response to NO (Aitken et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Nitric Oxide and Interleukin-1βStimulate the Proteasome-Independent Degradation of the Retinoic Acid Hydroxylase CYP2C22 in Primary Rat Hepatocytes

Lee

Arnold

et al. 2013

J Pharmacol Exp Ther

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CYP2C22 was recently described as a retinoic acid-metabolizing cytochrome P450 enzyme whose transcription is induced by alltrans-retinoic acid (atRA) in hepatoma cells (Qian L, Zolfaghari R, and Ross AC (2010) J Lipid Res 51:1781-1792). We identified CYP2C22 as a putative nitric oxide (NO)-regulated protein in a proteomic screen and raised specific polyclonal antibodies to CYP2C22 to study its protein expression. We found that CYP2C22 is a liver-specific protein that was not significantly induced by activators of the pregnane X receptor, constitutive androstane receptor, or peroxisome proliferator-activated receptor-a, but was downregulated to ,25% of control by the aryl hydrocarbon receptor agonist b-naphthoflavone in cultured rat hepatocytes. CYP2C22 protein and its mRNA both were induced by atRA in hepatocytes, with EC 50 of 100-300 nM, whereas the maximal extent of mRNA induction was twice that of the protein. CYP2C22 protein, but not its mRNA, was rapidly downregulated in hepatocytes by interleukin-1 (IL-1) or NOdonating compounds, and the downregulation by IL-1 was blocked by inhibition of NO synthases. The NO donor (Z)-1-[N-(3-aminopropyl)-N-(3-ammoniopropyl)amino]diazen-1-ium-1,2-diolate reduced the half-life of CYP2C22 from 8.7 to 3.4 hours in the presence of cycloheximide, demonstrating that NOdependent downregulation is due to stimulated proteolysis. No intermediate degradation products were detected. However, this degradation was insensitive to inhibitors of calpains or the canonical proteasomal or lysosomal pathways, indicating that NO-dependent degradation of CYP2C22 proceeds via a novel pathway.

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Roles of nitric oxide in inflammatory downregulation of human cytochromes P450

Cited by 48 publications

References 44 publications

Dual Mechanisms of CYP3A Protein Regulation by Proinflammatory Cytokine Stimulation in Primary Hepatocyte Cultures

Dual Mechanisms of CYP3A Protein Regulation by Proinflammatory Cytokine Stimulation in Primary Hepatocyte Cultures

M1 Polarization Bias and Subsequent Nonalcoholic Steatohepatitis Progression Is Attenuated by Nitric Oxide Donor DETA NONOate via Inhibition of CYP2E1-Induced Oxidative Stress in Obese Mice

Nitric Oxide and Interleukin-1βStimulate the Proteasome-Independent Degradation of the Retinoic Acid Hydroxylase CYP2C22 in Primary Rat Hepatocytes

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