The role of nitric oxide generation in interferon-evoked cytochrome P450 down-regulation

doi:10.1016/0192-0561(95)00083-6

International Journal of Immunopharmacology

Volume 17, Issue 12, December 1995, Pages 995-1000

International Journa...

https://doi.org/10.1016/0192-0561(95)00083-6 Get rights and content

Abstract

The down-regulation of cytochrome P450 during host defence involves one or more mediators of unknown source and identity. Owing to striking similarities in the features that are involved in the production of NO and the features involved in the down-regulation of cytochrome P450 we hypothesized that NO could be a mediator in the interferon-evoked loss of cytochrome P450. In these experiments the nitric oxide synthase inhibitor l-nitroarginine (5 mg/kg) failed to protect mice from the down-regulation of cytochrome P450, ethoxyresorufin dealkylase and para-nitrophenol hydroxylase in the liver following administration of the interferon inducer polyinosinic.polycytidylic acid. A higher dose of L-nitroarginine (30 mg/kg) given every 12 h for 3 days also did not protect against cytochrome P450 losses. In addition, no down-regulation of the enzyme was observed in animals treated with multiple doses of the NO-generating drugs glyceryl trinitrate (16 and 80 mg/kg given every 4 h for 16 h) and nitroprusside (20 and 100 mg/kg given every 4 h for 16 h). These results indicate that the down-regulation of cytochrome P450 by interferon or its inducers probably does not involve NO as a required intermediary.

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Citation Excerpt :
Although these studies implicated the role of NO in CYP downregulation several recent studies reported that NO is not required for the suppression of CYP by LPS or cytokines.25–27 In support for the NO‐independence suppression of CYP several studies have shown that inducible nitric oxide synthase (NOS2) inhibition had no effect on cytokine‐mediated downregulation of CYP‐catalyzed activities.28,29 On the other hand, with respect to phase II xenobiotic metabolizing enzymes, it has been reported that Nqo1 is sensitive to nitrosative stress and Nqo1 expression can be induced by NO through antioxidant response element (ARE).30
We previously demonstrated that tumor necrosis factor alpha (TNF‐α) and lipopolysaccharide (LPS) downregulate aryl hydrocarbon receptor (AhR)‐regulated genes, such as cytochrome P450 1a1 (Cyp1a1) and NADPH: quinone oxidoreductase 1 (Nqo1) gene expression, yet the mechanisms involved remain unknown. The correlation between the inflammation‐mediated suppression of AhR‐regulated genes and the TNF‐α or LPS‐induced nitric oxide (NO) production especially in murine hepatoma Hepa 1c1c7 cells has been questioned; therefore we investigated whether NO is involved in the modulation of Cyp1a1 and Nqo1 by TNF‐α or LPS in Hepa 1c1c7 cells. A significant dose‐dependent increase in the inducible nitric oxide synthase (NOS2) expression and NO production were observed by various concentrations of TNF‐α (1, 5, and 10 ng/mL) and LPS (1 and 5 µg/mL) which was completely inhibited by a NOS2 inhibitor, L‐N6‐(1‐iminoethyl) lysine (L‐NIL) (1 mM). Furthermore, TNF‐α and LPS significantly induced NOS2 expression. Both TNF‐α and LPS repressed the β‐naphthoflavone (βNF)‐mediated induction of Cyp1a1 and Nqo1 at mRNA and activity levels. The downregulation of Cyp1a1, but not Nqo1, was significantly prevented by L‐NIL. However, proxynitrite decomposer, iron tetrakis (N‐methyl‐4′‐pyridyl) porphyrinato (FeTMPyP) (5 µM) did not affect TNF‐α‐ and LPS‐mediated downregulation of Cyp1a1 and Nqo1 at mRNA and activity levels. These results show that NO, but not peroxynitrite, may be involved in TNF‐α‐ and LPS‐mediated downregulation of Cyp1a1 without affecting the downregulation of Nqo1. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 2795–2807, 2007
Down-regulation of cytochrome P450 proteins and its activities by Shiga-like toxin II from Escherichia coli O157:H7
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Thus, it is possible that SLT-II indirectly altered hepatic CYP contents and activities by these cytokines. In fact, injection of IL-1 [44–47], NO donors [48,49], or TNF-α [44,50] decreases certain CYP activities and/or their mRNA expressions, although it is difficult to distinguish which mediator(s) play(s) important roles in SLT-II-induced decreases in hepatic CYP content/activity. Thus, we investigated the involvement of these cytokines in SLT-II-induced changes of CYP contents and activity by using several cytokine inhibitors.
Escherichia coli O157:H7 infection frequently induces clinical complications such as hemolytic uremic syndromes and intestinal dysfunctions. These changes could alter the disposition of drugs, consequently changing their efficacy. However, the possible changes of drug-metabolizing activities by E. coli O157:H7 infection have not been addressed. Thus, we have investigated the effect of Shiga-like toxin type II (SLT-II), derived from E. coli O157:H7, on the hepatic cytochrome P450 (CYP) content and its activity in rats. SLT-II (2 μg per animal, i.v.) time-dependently decreased total CYP content and the contents of CYP2C11 and CYP3A2 in hepatic microsomal preparations up to 24 hr following injection. Consistently, SLT-II time-dependently decreased CYP activity in vivo, as represented by systemic clearance of antipyrine. An inhibitor of inducible nitric oxide synthase, S-methylisothiourea, restored the decreased systemic clearance of antipyrine by SLT-II, suggesting the involvement of the overproduction of nitric oxide by SLT-II. Moreover, dexamethasone restored the decreased systemic clearance of antipyrine by SLT-II. In the hepatic microsomal preparation, dexamethasone restored the SLT-II-induced decrease of CYP3A2 whereas S-methylisothiourea did not affect both CYP subtypes. Taken together, these results suggest that SLT-II might alter hepatic drug-metabolizing function during E. coli O157 infection and that more than one cytokines induced by SLT-II, including nitric oxide, might make a critical contribution to the decrease of CYP content and its activity.
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During infection or inflammation, the expression of cytochrome P450 and its dependent biotransformation pathways are modified. This results in a change in the capacity of the liver to handle drugs and in alterations in the production and elimination of endogenous substances throughout the body. The majority of the CYP isoforms are modified at pre-translational steps in protein synthesis, and, in most cases, cytokines are involved as mediators of the response. Recent information suggests that inflammatory responses that are localized to the CNS cause a loss of CYP within the brain. This is accompanied by a parallel down-regulation of CYP in peripheral organs that is mediated by a signaling pathway between the brain and periphery. This review covers the loss that occurs in the major mammalian CYP families in response to infection/inflammation and the mediator pathways that are key to this response.
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In this study, we attempted to determine the effect of a systemic infection with Chlamydia trachomatis on cytochrome P450(CYP)-dependent metabolism in mice. Furthermore, we wanted to assess if these effects were mediated through NO. BALB/c(H-2d) female mice were inoculated intraperitoneally with the C. trachomatis mouse pneumonitis (MoPn) biovar, and induction of NO synthase (NOS) was detected by measuring [NO_x] levels and inducible NOS protein content in peritoneal macrophages by Western blotting. Recovery of C. trachomatis from liver, lung, and spleen peaked at 4 days postinfection. Following cotreatment with N^G-nitro-l-arginine methyl ester (l-NAME), an inhibitor of NO synthase, there was a significant increase in the intensity and the length of the infection. Six days after inoculation with C. trachomatis, CYP1A- and CYP2B-mediated metabolism in the liver of the mice was diminished up to 49% of control levels. However, when animals were treated with N^G-nitro-l-arginine methyl ester at days 4 and 6 postinfection, the decrease in the metabolism of CYP1A and CYP2B was largely blocked. These results suggest that C. trachomatis infection can depress cytochrome P450 in a manner similar to other types of infections and that NO is likely to be a mediator of this depression. This finding may be of significance to patients taking drugs that are metabolized by phase I enzymes during infections with some bacteria such as C. trachomatis.
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Research paperThe role of nitric oxide generation in interferon-evoked cytochrome P450 down-regulation

Abstract

Lancet

Biochem. Pharmac.

J. biol. Chem.

J. biol. Chem.

Biochem. Pharmac.

Biochem. biophys. Res. Commun.

Arch. biochem. Biophys.

Characteristics of a microsomal cytochrome P448 mediated reaction ethoxyresorufin O-de-ethylation

Drug Metab. Dispos.

Nitric oxide: a physiologic mediator of penile erection

Science

Interferon down regulation the male specific cytochrome P-450 IIIA2 in rat liver

Molec. Pharmac.

Nitric oxide and nitric oxide generating compounds inhibit hepatocyte protein synthesis

FASEB J.

Sustained hypertension induced by orally administered nitro-l-arginine

Hypertension

Temporal changes in the microsomal drug metabolizing system of the liver during sexual maturation

Drug Metab. Dispos.

Effect of murine gamma-interferon on the mouse liver and its drug-metabolizing enzymes: comparison with human hybrid alpha-interferon

J. Interferon Res.

Nitric oxide: a cytotoxic activated macrophage effector molecule

Biochem. biophys. Res. Commun.

Nitric oxide is a mediator of the decrease in cytochrome P450-dependent metabolism caused by immunostimulants

Research paper
The role of nitric oxide generation in interferon-evoked cytochrome P450 down-regulation