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Cytochrome P450 Dependent N-hydroxylation Of A Guanidine (debrisoquine), Microsomal Catalysed Reduction And Further Oxidation Of The N-hydroxy-guanidine Metabolite To The Urea Derivative. Similarity With The Oxidation Of Arginine To Citrulline And Nitric Oxide.
B. Clement, M. Schultze-Mosgau, H. Wohlers
Published 1993 · Chemistry, Medicine
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The microsomal N-hydroxylation of the strongly basic guanidinium group (debrisoquine) to N-hydroxyguanidine (N-hydroxydebrisoquine) and the retroreduction of the N-hydroxyguanidine are demonstrated for the first time. The reduction of the N-hydroxyguanidine by liver homogenates and hepatocytes is catalysed by a microsomal NADH-dependent system that is strongly inhibited by hydroxylamine or N-methylhydroxylamine. In the presence of these alternate substrates for the reductase the microsomal catalysed N-hydroxylation of debrisoquine is readily characterized. The oxidation was inhibited by antibodies against NADPH cytochrome P450 reductase and the role of the P450 monooxygenase was further verified by studies with partially purified and purified P450 2C3 reconstituted systems. The transformation of N-hydroxydebrisoquine to the corresponding urea derivative was also detected in in vitro experiments with microsomal fractions and enriched P450 fractions as well as with flavin-containing monooxygenase (FMO). Experiments with catalase, superoxide dismutase and H2O2 have shown that the H2O2 or O2-, respectively, formed from the respective enzyme and the substrate, apparently participated in the reaction. Whereas the N-hydroxylation of the guanidine involves the usual monooxygenase activity of cytochrome P450 the resultant N-hydroxyguanidine decouples monooxygenases (cytochrome P450, FMO) and the H2O2 and, above all, O2- thus formed transform the N-hydroxyguanidine further to the corresponding urea derivative. The possibility for the N-hydroxylation of non-physiological guanidines to N-hydroxyguanidines and subsequent oxidative conversion to the respective urea is comparable to the physiological transformation of arginine to citrulline via N-hydroxyarginine with the liberation of nitric oxide (endothelial derived relaxing factor) and could, therefore, contribute to the efficacy of drugs containing guanidine and similar functional groups.
This paper references
Microsomal triphosphopyridine nucleotide-cytochrome c reductase of liver.
C. Williams (1962)
THE CARBON MONOXIDE-BINDING PIGMENT OF LIVER MICROSOMES. I. EVIDENCE FOR ITS HEMOPROTEIN NATURE.
T. Omura (1964)
Properties of a NADH-dependent N-hydroxy amine reductase isolated from pig liver microsomes.
F. Kadlubar (1974)
POLYMORPHIC HYDROXYLATION OF DEBRISOQUINE IN MAN
A. Mahgoub (1977)
Species variations in the N-oxidation of chlorphentermine.
J. Caldwell (1975)
In vitro oxygenation of N,N'-diphenylguanidines.
B. Clement (1993)
Chemical oxidation of N-hydroxyguanidine compounds. Release of nitric oxide, nitroxyl and possible relationship to the mechanism of biological nitric oxide generation.
J. Fukuto (1992)
Some properties of a detergent-solubilized NADPH-cytochrome c(cytochrome P-450) reductase purified by biospecific affinity chromatography.
Y. Yasukochi (1976)
Genotoxic activities of benzamidine and itsN-hydroxylated metabolite benzamidoxime inSalmonella typhimurium and mammalian cells
B. Clément (1988)
In‐vitro‐Untersuchungen zur mikrosomalen N‐Oxidation einiger Guanidine
B. Clement (1986)
The rabbit pulmonary monooxygenase system. Immunochemical and biochemical characterization of enzyme components.
C. Serabjit-Singh (1979)
N omega-hydroxy-L-arginine: a novel arginine analog capable of causing vasorelaxation in bovine intrapulmonary artery.
G. C. Wallace (1991)
Cytochrome P-455 nm complex formation in the metabolism of phenylalkylamines. XI. Peroxygenase versus monooxygenase function of cytochrome P-450 in rat liver microsomes.
K. Jönsson (1990)
Chemical mechanisms of catalysis by cytochromes P-450: a unified view
F. Guengerich (1984)
Two catalytically distinct subforms of cytochrome P-450 3b as obtained from inbred rabbits.
G. Schwab (1985)
New aspects of the microsomal N -hydroxylation of benzamidines
B. Clement (1991)
Irreversible inactivation of macrophage and brain nitric oxide synthase by L-NG-methylarginine requires NADPH-dependent hydroxylation.
P. Feldman (1993)
Enzymatic Reduction of Benzamidoxime to Benzamidoxine
B. Clement (1988)
Formation of nitric oxide by cytochrome P450-catalyzed oxidation of aromatic amidoximes.
V. Andronik-Lion (1992)
Macrophage oxidation of L-arginine to nitrite and nitrate: nitric oxide is an intermediate.
M. Marletta (1988)
Measurement of protein using bicinchoninic acid.
P. Smith (1985)
Superoxide radical as an intermediate in the oxidation of hydroxylamines by mixed function amine oxidase.
E. Rauckman (1979)
Flavin-containing monooxygenases: catalytic mechanism and substrate specificities.
D. Ziegler (1988)
The N-oxidation of benzamidines in vitro.
B. Clement (1983)
Stickoxid‐freisetzende Substanzen und Inhibitoren der NO‐Synthase
R. Henning (1993)
Hepatic microsomal cytochrome p-450-dependent N-demethylation of methylguanidine.
Kawata Sumio (1983)
Assay of debrisoquine and 4-hydroxydebrisoquine in urine by reversed-phase high-performance liquid chromatography using on-line sample clean-up on a standard isocratic chromatograph.
J. Moncrieff (1988)
The mechanistic plurality of cytochrome P-450 and its biological ramifications.
J. Capdevila (1984)
Studies on the N -oxidation of phentermine: evidence for an indirect pathway of N -oxidation mediated by cytochrome P -450
A. Cho (1991)
N-hydroxylation of benzamidine to benzamidoxime by a reconstituted cytochrome P-450 oxidase system from rabbit liver: involvement of cytochrome P-450 IIC3.
B. Clement (1993)
Vascular endothelial cells synthesize nitric oxide from L-arginine
R. M. Palmer (1988)
15N‐NMR‐Studien an 2‐Hydroxyguanidinen und Amidoximen
B. Clement (1985)
Formation of nitrogen oxides and citrulline upon oxidation of N omega-hydroxy-L-arginine by hemeproteins.
J. L. Boucher (1992)
Cytochrome P450 catalyzes the oxidation of N omega-hydroxy-L-arginine by NADPH and O2 to nitric oxide and citrulline.
J. L. Boucher (1992)
Induction of liver cytochrome P-450 in mice by warfarin. Comparison of warfarin-, phenobarbitone-, and cobalt-induced hepatic microsomal protein patterns by PAGE after partial purification on octyl-sepharose CL-4B.
L. Kling (1985)
Hepatic microsomal N-demethylation of N-methylbenzamidine. N-dealkylation vs N-oxygenation of amidines.
B. Clement (1987)
Preparation of isolated rat liver cells.
P. Seglen (1976)
Determination of serum proteins by means of the biuret reaction.
A. Gornall (1949)
Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4
U. Laemmli (1970)
Ueber das Tetrahydrür des Isochinolins
E. Bamberger (1893)
Biotransformations of Benzamidine and Benzamidoxime in vivo
B. Clement (1993)
Reduced pyridine nucleotide-dependent N-hydroxy amine oxidase and reductase activities of hepatic microsomes.
F. Kadlubar (1973)
N omega-hydroxy-L-arginine is an intermediate in the biosynthesis of nitric oxide from L-arginine.
D. Stuehr (1991)
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B. Clement (1994)
Metabolismus und Bioverfügbarkeit von Serinprotease Inhibitoren und ihren Amidoxim-Prodrugs
Joscha Kotthaus (2008)
The soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a] quinoxalin-1-one is a nonselective heme protein inhibitor of nitric oxide synthase and other cytochrome P-450 enzymes involved in nitric oxide donor bioactivation.
M. Feelisch (1999)
Prodrug design for the potent cardiovascular agent Nω-hydroxy-L-arginine (NOHA): synthetic approaches and physicochemical characterization.
D. Schade (2011)
Nδ-Methylated l-arginine derivatives and their effects on the nitric oxide generating system
J. Kotthaus (2008)
Enhancement of methylcholanthrene-induced neoplastic transformation in murine C3H 10T1/2 fibroblasts by antisense phosphorothioate oligodeoxynucleotide sequences.
L. A. Lesoon-Wood (1999)
New NO‐Donors with Antithrombotic and Vasodilating Activities, Part 17. Arylazoamidoximes and 3‐Arylazo‐1,2,4‐oxadiazol‐5‐ones
K. Rehse (1997)
NADH-dependent reduction of sulphamethoxazole hydroxylamine in dog and human liver microsomes
L. Trepanier (2000)
Microsomal formation of nitric oxide and cyanamides from non-physiological N-hydroxyguanidines: N-hydroxydebrisoquine as a model substrate.
B. Clement (1999)
Oxygen-insensitive enzymatic reduction of oximes to imines.
Sabine Heberling (2006)
Heme-Thiolate Proteins Differentfrom Cytochromes P450 Catalyzing
D. Mansuy (1995)
Heme-Thiolate Proteins Different from Cytochromes P450 Catalyzing Monooxygenations
D. Mansuy (1995)
Uptake, translocation and possible biodegradation of the antidiabetic agent metformin by hydroponically grown Typha latifolia.
H. Cui (2016)
Cellular nitrogen oxide production: Its role in endogeneous mutation and carcinogenesis
R. Cooney (1995)
Regioselective hydroxylation of debrisoquine by cytochrome P4502D6: implications for active site modelling
T. Lightfoot (2000)
Reduction of hydroxamic acids to the corresponding amides catalyzed by rabbit blood
K. Sugihara (2000)
New NO‐Donors with Antithrombotic and Vasodilating Activities, Part 14 1,3,4‐Triazol‐1‐oles
K. Rehse (1996)
A unique tertiary amine N-oxide reduction system composed of quinone reductase and heme in rat liver preparations.
S. Kitamura (1999)
Untersuchung von potentiellen NO-Donoren hinsichtlich ihres NO-Freisetzungsmusters und ihrer Simulationsfähigkeit mittels ausgewählter in-vitro-Methoden
Christin Erbach (1999)
5.05 – Principles of Drug Metabolism 1: Redox Reactions
W. Trager (2007)
Vasorelaxant activity of some oxime derivatives.
F. Jaroš (2007)
Cytochrome P450 Catalyzed Nitric Oxide Synthesis: A Theoretical Study
G. Keserü (2000)
Ligands representing important functional groups of natural organic matter facilitate Fe redox transformations and resulting binding environments
A. Bhattacharyya (2019)
Multiple Mechanisms of Cancer Prevention by Phytochemicals: Interaction Between Cellular Proliferation and Endogenous Mutagens
R. Cooney (1997)
METABOLISM OF N-HYDROXYGUANIDINES (N-HYDROXYDEBRISOQUINE) IN HUMAN AND PORCINE HEPATOCYTES: REDUCTION AND FORMATION OF GLUCURONIDES
A. K. Froehlich (2005)
Formation of nitrogen oxides including NO from oxidative cleavage of CN(OH) bonds: A general cytochrome P450-dependent reaction.
A. Jousserandot (1995)
On the mechanism of nitric oxide formation upon oxidative cleavage of C = N(OH) bonds by NO-synthases and cytochromes P450.
D. Mansuy (1995)
Nitric Oxide Donor Activity of Antihypertensive Drugs Guanoxan, Guanabenz, and Moxonidine
A. Danilov (2004)
REDUCTION OF N-HYDROXYLATED COMPOUNDS: AMIDOXIMES (N-HYDROXYAMIDINES) AS PRO-DRUGS OF AMIDINES
B. Clement (2002)
P216 genotoxic activities of N-hydroxylated derivatives of amidines, guanidines and amidinohydrazones in salmonella typhimurium
B. Clement (1994)
Chemistry of N-hydroxy-L-arginine.
J. Fukuto (1996)
Chapter 9. The Enzymology and Manipulation of Nitric Oxide Synthase
J. Fukuto (1994)See more