114. The reaction of phenylhydroxylamine and 2-naphthylhydroxylamine with thiols

Boyland, E.; Manson, D.; Nery, Rosane Maria

doi:10.1039/jr9620000606

Cited by 41 publications

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“…The cycle is depleted eventually by side reactions involving phenylhydroxylamine or nitrosobenzene, or by reduction of phenylhydroxylamine to aniline within erythrocytes (Eyer [17], Kiese [5], Murayama [18]). Side reactions which may occur within erythrocytes include binding of phenylhydroxylamine to erythrocytic protein (Kiese and Traeger [19] and binding of both nitrosobenzene and phenylhydroxylamine to sulfhydryl groups in glutathione or protein (Boyland et al [20], Eyer [17). The findings presented here support that several aniline metabolites of known structure mediate the hemolytic effect of aniline or any aniline-related compounds.…”

Section: Hemolytic Anemiasupporting

confidence: 60%

Methemoglobin and hemolytic anemia as potential markers for drug side-effects

Singh

Purnell

2005

Environmental Health Risk III

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Methemoglobinemia and hemolytic anemia are the most prominent side-effects of a wide variety of arylamine drugs including agricultural and industrial chemicals. Symptoms of this hemotoxicity include headache, fatigue, dizziness respiratory and cardiac arrest, and possibly death. Parent compounds are usually converted to their toxic metabolites (N-hydroxylamine) and react with oxyhemoglobin with the consequent reduction of molecular oxygen to active oxygen species leading to hemotoxic damage. We are investigating the role of redox cycling and an alternative hypothesis; viz., that a "hydroxylaminecentered" radical formed during an arylhydroxylamine-oxyhemoglobin reaction causes hemotoxic damage. We examined the time-course methemoglobin potential and hemolytic anemia potential of four laboratory synthesized halogenated phenylhydroxylamines based on their decreasing electronegativity: phenylhydroxylamine (PHA), p-fluoro-, p-bromo-, and p-iodo-PHA. Methemoglobin (MetHb) was determined spectrophotometrically and erythrocyte hemolysis was studied by collecting whole blood from male Sprague-Dawley rats, labeling the cells with radioactive chromium-51 and by infusing the labeled erythrocytes via tail vein in isologous rats. The time course of blood radioactivity was followed by serial sampling of blood from the orbital sinus for 14 days. Results showed dose-and time-dependent changes in the induction of methemoglobin by aniline-derivatives. The MetHb levels peaked to more than 70 percent within 10 minutes at 60 µM and remained elevated for 240 minutes in certain treatments. All tested agents produced dose-dependent reductions in the labeled red blood cells indicating the loss of blood cells from circulation. The dose-and time-dependent methemoglobin and hemolytic anemia responses suggest these hydroxylamines as potential active metabolites and biomarkers that may mediate aniline-induced hemotoxicity. The minimum dose required to induce these effects varies with the test agent based on their electronegativity potential.

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Section: Hemolytic Anemiasupporting

confidence: 60%

Methemoglobin and hemolytic anemia as potential markers for drug side-effects

Singh

Purnell

2005

Environmental Health Risk III

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“…(Received 13 July 1962) The findings of Cramer, Miller & Miller (1960) and of Nelson & Troll (1961) that 2-acetamidofluorene and 2-naphthylamine respectively are metabolized by N-hydroxylation, and of Boyland & Manson (1961) that 2-naphthylhydroxylamine sulphate is excreted by dogs dosed with 2-naphthylamine, indicated that arylhydroxylamines are intermediates in the metabolism of arylamines. Arylhydroxylamines are reactive compounds; they react with cysteine to give S-(aminoaryl)cysteine derivatives and with acetylcysteine to give aminoarylmercapturic acids (Boyland, Manson & Nery, 1962). Because of this reaction it seemed probable that aromatic amines would be excreted as mercapturic acids, and a product which appears to be (2-amino-l-naphthyl)mercapturic acid has been detected in the urine of dogs and rats treated with 2-naphthylamine.…”

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confidence: 99%

The biochemistry of aromatic amines. 9. Mercapturic acids as metabolites of aniline and 2-naphthylamine

Boyland¹,

Manson²,

Nery³

1963

Biochemical Journal

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“…The metabolite retained its radioactivity whether it was derived from [ethyl-14C]phenacetin or [acetyl-3H]phenacetin, indicating that it might be a 4-ethoxyacetanilido derivative. Deoxygenation of the metabolite with phosphorus trichloride gave a product that was chromatographically identical with a product [probable structure (II)] obtained from the reaction between N-acetoxyphenacetin (IV) and N-acetylcysteine, the structure (II) being indicated by analogy with known reactions of arylhydroxylamines with thiols (Boyland, Manson & Nery, 1962 and with other nucleophilic reagents (Hughes & Ingold, 1952;; oxidation of the product with hydrogen peroxide gave a substance that was chromatographically identical with the metabolite. An acid hydrolysate of the metabolite contained a product [probably compound (III)] giving positive reactions with reagents (iii) (indicating an aromatic amino group) and (v) (indicating an amino acid).…”

Section: Metaboli8m Of [Acetyl3h]phenacetin Four 6-mentioning

confidence: 93%

Some new aspects of the metabolism of phenacetin in the rat

Nery

1971

Biochemical Journal

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1. Four new metabolites of phenacetin in the urine of the rat are described; these are (i) N-acetyl-S-ethylcysteine, (ii) quinol, (iii) acetamide and (iv) probably N-acetyl-S-2-(4-ethoxyacetanilido)cysteine S-oxide. 2. Metabolites (i), (iii) and (iv) were characterized and estimated by g.l.c., by t.l.c., by paper chromatography, by chemical reactions or by radioactive techniques after administration to rats of [ethyl-(14)C]phenacetin and [acetyl-(3)H]phenacetin; metabolite (ii), which was excreted mainly as conjugates of sulphuric acid and glucosiduronic acid, was measured by paper chromatography and characteristic colour reactions after enzymic and chemical hydrolysis of the conjugates. 3. Small amounts of azoxy-4-[ethyl-(14)C]ethoxybenzene and an unknown metabolite were also found in the urine of rats after administration of [ethyl-(14)C]phenacetin. 4. The likely mechanisms and some biological implications of these metabolic reactions are discussed.

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114. The reaction of phenylhydroxylamine and 2-naphthylhydroxylamine with thiols

Cited by 41 publications

References 0 publications

Methemoglobin and hemolytic anemia as potential markers for drug side-effects

Methemoglobin and hemolytic anemia as potential markers for drug side-effects

The biochemistry of aromatic amines. 9. Mercapturic acids as metabolites of aniline and 2-naphthylamine

Some new aspects of the metabolism of phenacetin in the rat

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