Nitric oxide complexes of cytochrome <i>P</i>‐450

Ebel, Richard E.; O'Keeffe, David H.; Peterson, Julian A.

doi:10.1016/0014-5793(75)80991-4

Cited by 75 publications

(29 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…NO can modulate the activity of CYP-450 by forming complexes with the iron in the heme moiety of these enzymes (Ebel et al 1975), and NO released from NO donors, such as NOC7, sodium nitroprusside, and SNAP, inhibits CYP-450 (Donato et al 1997;Gergel et al 1997). In agreement with this finding, endogenous NO formation contributes to the rapid loss of CYP-450 activity in cultured hepatocytes (López-García 1998), and enhanced NO production accounts for the inhibition of CYP-450 expression and activity in response to cytokines (tumor necrosis factor-a, interleukin-1β, and interferon-+; Stadler et al 1994;Carlson and Billings 1996;Donato et al 1997) and to Escherichia coli LPS (Takemura et al 1999) in vitro.…”

Section: Discussionmentioning

confidence: 99%

Hepatic morphological alterations, glycogen content and cytochrome P450 activities in rats treated chronically with Nω-nitro-L-arginine methyl ester (L-NAME)

et al. 2007

View full text Add to dashboard Cite

Chronic treatment of rats with N(omega)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) biosynthesis, results in hypertension mediated partly by enhanced angiotensin-I-converting enzyme (ACE) activity. We examined the influence of L-NAME on rat liver morphology, on hepatic glycogen, cholesterol, and triglyceride content, and on the activities of the cytochrome P450 isoforms CYP1A1/2, CYP2B1/2, CYP2C11, and CYP2E1. Male Wistar rats were treated with L-NAME (20 mg/rat per day via drinking water) for 2, 4, and 8 weeks, and their livers were then removed for analysis. Enzymatic induction was produced by treating rats with phenobarbital (to induce CYP2B1/2), beta-naphthoflavone (to induce CYP1A1/2), or pyrazole (to induce CYP2E1). L-NAME significantly elevated blood pressure; this was reversed by concomitant treatment with enalapril (ACE inhibitor) or losartan (angiotensin II AT(1) receptor antagonist). L-NAME caused vascular hypertrophy in hepatic arteries, with perivascular and interstitial fibrosis involving collagen deposition. Hepatic glycogen content also significantly increased. L-NAME did not affect fasting glucose levels but significantly reduced insulin levels and increased the insulin sensitivity of rats, based on an intraperitoneal glucose tolerance test. Immunoblotting experiments indicated enhanced phosphorylation of protein kinase B and of glycogen synthase kinase 3. All these changes were reversed by concomitant treatment with enalapril or losartan. L-NAME had no effect on hepatic cholesterol or triglyceride content or on the basal or drug-induced activities and protein expression of the cytochrome P450 isoforms. Thus, the chronic inhibition of NO biosynthesis produced hepatic morphological alterations and changes in glycogen metabolism mediated by the renin-angiotensin system. The increase in hepatic glycogen content probably resulted from enhanced glycogen synthase activity following the inhibition of glycogen synthase kinase 3 by phosphorylation.

show abstract

Section: Discussionmentioning

confidence: 99%

Hepatic morphological alterations, glycogen content and cytochrome P450 activities in rats treated chronically with Nω-nitro-L-arginine methyl ester (L-NAME)

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Immunostimulants induce the expression of a highoutput, Ca2+-independent isoform of NOS in many cell types, including hepatocytes and Kupffer cells (25)(26)(27). Before the discovery of NO as a biosignaling molecule, NO was known to bind with great avidity to the heme iron of hemoproteins (2, 3), including cytochromes P450 (28). We and Wink et al (29) have shown that NO, in supraphysiological concentrations, will impair cytochrome P450-mediated metabolism by isolated hepatic microsomes.…”

Section: Discussionmentioning

confidence: 99%

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

Khatsenko

Gross

Rifkind

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

258

128

View full text Add to dashboard Cite

Bacterial lipopolysaccharide (LPS) and a diverse array of other immunostimulants and cytokines suppress the metaboism of endogenous and exogenous substances by reducing activity of the hepatic cytochrome P450 mixedfunction oxidase system. Although this effect of immunostimulants was first described almost 40 yr ago, the mechanism is obscure. Immunostimulants are now known to cause NO overproduction by celis via induction of nitric oxide synthase.We have investigated whether NO overproduction is involved in suppressing hepatic metabolism by LPS. In vitro treatment of hepatic microsomes with NO, produced by chemical decomposition of 3-morpholinosydnonimnue or by nitric oxide synthase, substantially suppressed cytochrome P450-dependent oxygenation reactions. This effect of NO was seen with hepatic microsomes prepared from two species (rat and chicken) and after exposure to chemicais that induce distinct molecular isoforms of cytochromes P450 (-naphthoflavone, 3-methylcholanthrene, and phenobarbital). Spectral studies indicate that NO reacts in vitro with both Fe2+-and Fe3+-hemes in microsomal cytochromes P450. In vivo, LPS diminished the phenobarbital-induced dealkylation of 7-pentoxyresorufin by rat liver microsomes and reduced the apparent P450 content as measured by CO binding. These LPS effects were associated with induction of NO synthesis; LPS-induced NO synthesis showed a strong positive correlation with the severity of cytochrome P450 inhibition. The decrease in both hepatic microsomal P450 activity and CO binding caused by LPS was largely prevented by the selective NO synthase inhibitor N"-nitro-L-arginine methyl ester. Our rmdings implicate NO overproduction as a major factor mediating the suppression of hepatic metabolism by immunostimulants such as LPS.NO is a secretory product of mammalian cells that is important in the regulation of vascular tone, platelet function, neurotransmission, and host-defense mechanisms (1-3). These physiological actions are attributable to the oxidation by NO of heme and nonheme iron and iron-sulfur complexes in the active sites of key metabolic enzymes. Thus, through its interaction with iron, NO modulates the activity of target proteins. Although NO is normally produced in relatively small quantities and presumably by particular cell types (e.g., endothelial cells and neurons), NO (PB) (CYP2B1/2), (-naphthoflavone (3-NF), and 3-methylcholanthrene (3-MC) (CYPlA1/2) (4-7).Immunological stimuli depress cytochrome P450-mediated hepatic metabolism of a variety of drugs and endogenous substances. Indeed, attenuated cytochrome P450 activity has been seen in animals after infection with bacteria and viruses or after treatment with cytokines (e.g., interleukin 1; interferon 'y, tumor necrosis factor a) and immunostimulants (e.g., LPS and single-stranded RNA) (8, 9). Despite wide acceptance that the immune system can inhibit hepatic drug metabolism, the mechanism of this effect is largely unknown. Our study reveals that NO, produced by immunoactivated cells, mediates sup...

show abstract

“…It is well established that NO is capable of binding to a variety of proteins which otherwise bind and reduce O 2 . For example, NO forms stable nitrosyl complexes with cytochrome c oxidase (16,41) and cytochrome P450 (42)(43)(44), two primary O 2 -binding and O 2 -reducing proteins, and formation of these complexes has been implicated in the inhibition of their activity. Up to now, it has been difficult to reconcile the observation that NO was capable of binding at the O 2 binding site of these redox proteins and yet was not readily reduced, as (i) NO binds with high affinity to the O 2 -reducing proteins; and (ii) based on its previously reported reduction potentials, the reduction of NO should be thermodynamically more facile than that of O 2 .…”

Section: Discussionmentioning

confidence: 99%

The reduction potential of nitric oxide (NO) and its importance to NO biochemistry

Bartberger

Liu

Ford

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

352

269

View full text Add to dashboard Cite

A potential of about ؊0.8 (؎0.2) V (at 1 M versus normal hydrogen electrode) for the reduction of nitric oxide (NO) to its one-electron reduced species, nitroxyl anion ( 3 NO ؊ ) has been determined by a combination of quantum mechanical calculations, cyclic voltammetry measurements, and chemical reduction experiments. This value is in accord with some, but not the most commonly accepted, previous electrochemical measurements involving NO. Reduction of NO to 1 NO ؊ is highly unfavorable, with a predicted reduction potential of about ؊1.7 (؎0.2) V at 1 M versus normal hydrogen electrode. These results represent a substantial revision of the derived and widely cited values of ؉0.39 V and ؊0.35 V for the NO͞ 3 NO ؊ and NO͞ 1 NO ؊ couples, respectively, and provide support for previous measurements obtained by electrochemical and photoelectrochemical means. With such highly negative reduction potentials, NO is inert to reduction compared with physiological events that reduce molecular oxygen to superoxide. From these reduction potentials, the pKa of 3 NO ؊ has been reevaluated as 11.6 (؎3.4). Thus, nitroxyl exists almost exclusively in its protonated form, HNO, under physiological conditions. The singlet state of nitroxyl anion, 1 NO ؊ , is physiologically inaccessible. The significance of these potentials to physiological and pathophysiological processes involving NO and O 2 under reductive conditions is discussed. N itric oxide (NO) is an endogenously generated species with a diverse array of biological functions (1). NO is one of the primary regulators of vascular tone, is involved in signal transduction in both the peripheral and central nervous system, and is an integral part of the immune response system associated with macrophage and neutrophil activation. More recently, NO has been proposed to be involved in the regulation of mitochondrial function (2, 3). Problems in NO homeostasis have been implicated in the development of a variety of diseases and disorders such as hypertension and atherosclerosis (4), diabetes (5), and many neurodegenerative diseases (6). NO is also thought to be a cytoprotective agent, capable of inhibiting radical-induced damage and oxidative stress (7). To understand the actions of NO as a physiological messenger and a cytotoxic or cytoprotective effector molecule, it is essential to understand its basic chemical interactions with biological systems and its metabolic fate.NO and its reduced derivative NO Ϫ (and͞or its conjugate acid, HNO) have very different chemical properties and display distinct and often opposite effects in cells. For example, HNO͞ NO Ϫ has been found to be toxic under conditions where NO is cytoprotective (8). HNO͞NO Ϫ reacts with O 2 to generate potent oxidizing species, capable of damaging DNA and causing cellular thiol depletion, whereas NO does neither under similar conditions (9-11). HNO has been found to be a thiophilic electrophile (12), readily capable of modifying cellular thiol functions (13,14), whereas NO reacts only indirectly with thiols. HNO͞NO Ϫ h...

show abstract

Nitric oxide complexes of cytochrome P‐450

Cited by 75 publications

References 15 publications

Hepatic morphological alterations, glycogen content and cytochrome P450 activities in rats treated chronically with Nω-nitro-L-arginine methyl ester (L-NAME)

Hepatic morphological alterations, glycogen content and cytochrome P450 activities in rats treated chronically with Nω-nitro-L-arginine methyl ester (L-NAME)

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

The reduction potential of nitric oxide (NO) and its importance to NO biochemistry

Contact Info

Product

Resources

About