Phenylhydroxylamine

Role in aniline-associated splenic oxidative stress and induction of subendocardial necrosis

M Khan, S. M. Green, Ghulam Ansari, Paul J. Boor

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

To elucidate the role of N-phenylhydroxylamine (PHA, N-hydroxylated metabolite of aniline) in the selective toxicity of aniline to the spleen, dose-dependent studies were conducted with PHA in rats. Male Sprague-Dawley rats were given four doses each (1 dose/day) of 0.025, 0.05, 0.1, or 0.2 mmol/kg PHA in 0.5 ml of aqueous agar (0.25%) by gavage. The control animals received an equal volume of vehicle only. The animals were euthanized 24 h following the last dose. PHA toxicity in the blood was evident from a dose- dependent increase of methemoglobin. The most affected organ was spleen, which appeared dark and enlarged (splenomegaly) and showed increased spleen- to-body weight ratios, which were 28, 40, 66, and 87% at PHA doses of 0.025, 0.05, 0.1, and 0.2 mmol/kg, respectively. Splenic lipid peroxidation (malondialdehyde content) was higher in all PHA-treated groups, whereas splenic protein oxidation (carbonyl content) increased in only the 0.05, 0.1, and 0.2 mmol/kg groups. The total iron content in the spleen also showed increases of 88, 135, 168, and 209% at PHA doses of 0.025, 0.05, 0.1, and 0.2 mmol/kg, respectively. These biochemical changes were accompanied by a dose- dependent vascular congestion in the spleen, a characteristic feature of aniline toxicity. Although the ratio of organ to body weight increased for both testes and heart at the highest dose, striking morphological changes were observed only in heart. The cardiac lesions consisted of a both acute and resolving multifocal subendocardial necrosis involving predominently the left ventricle. Our results suggest that PHA is a splenotoxin and thus contributes to the toxicity of aniline, while at a high dose, it is also cardiotoxic, perhaps due to anoxia associated with the marked methemoglobinemia. These results further support the involvement of oxidative stress in the splenotoxicity of aniline which may be caused by its reactive metabolite(s) such as PHA.

Original languageEnglish (US)
Pages (from-to)64-71
Number of pages8
JournalToxicological Sciences
Volume42
Issue number1
DOIs
StatePublished - Mar 1998

Fingerprint

Oxidative stress
Oxidative Stress
Necrosis
Spleen
Toxicity
Metabolites
Rats
Animals
Body Weight
Methemoglobinemia
Methemoglobin
Splenomegaly
Malondialdehyde
Lipid Peroxidation
Agar
Heart Ventricles
Blood Vessels
Sprague Dawley Rats
Testis
Blood

Keywords

  • Aniline
  • Lipid peroxidation
  • Myocardial necrosis
  • Oxidative stress
  • Phenylhydroxylamine
  • Protein oxidation
  • Spleen

ASJC Scopus subject areas

  • Toxicology

Cite this

Phenylhydroxylamine : Role in aniline-associated splenic oxidative stress and induction of subendocardial necrosis. / Khan, M; Green, S. M.; Ansari, Ghulam; Boor, Paul J.

In: Toxicological Sciences, Vol. 42, No. 1, 03.1998, p. 64-71.

Research output: Contribution to journalArticle

@article{34fd9bf7db90458ab820aed009fa1a8c,
title = "Phenylhydroxylamine: Role in aniline-associated splenic oxidative stress and induction of subendocardial necrosis",
abstract = "To elucidate the role of N-phenylhydroxylamine (PHA, N-hydroxylated metabolite of aniline) in the selective toxicity of aniline to the spleen, dose-dependent studies were conducted with PHA in rats. Male Sprague-Dawley rats were given four doses each (1 dose/day) of 0.025, 0.05, 0.1, or 0.2 mmol/kg PHA in 0.5 ml of aqueous agar (0.25{\%}) by gavage. The control animals received an equal volume of vehicle only. The animals were euthanized 24 h following the last dose. PHA toxicity in the blood was evident from a dose- dependent increase of methemoglobin. The most affected organ was spleen, which appeared dark and enlarged (splenomegaly) and showed increased spleen- to-body weight ratios, which were 28, 40, 66, and 87{\%} at PHA doses of 0.025, 0.05, 0.1, and 0.2 mmol/kg, respectively. Splenic lipid peroxidation (malondialdehyde content) was higher in all PHA-treated groups, whereas splenic protein oxidation (carbonyl content) increased in only the 0.05, 0.1, and 0.2 mmol/kg groups. The total iron content in the spleen also showed increases of 88, 135, 168, and 209{\%} at PHA doses of 0.025, 0.05, 0.1, and 0.2 mmol/kg, respectively. These biochemical changes were accompanied by a dose- dependent vascular congestion in the spleen, a characteristic feature of aniline toxicity. Although the ratio of organ to body weight increased for both testes and heart at the highest dose, striking morphological changes were observed only in heart. The cardiac lesions consisted of a both acute and resolving multifocal subendocardial necrosis involving predominently the left ventricle. Our results suggest that PHA is a splenotoxin and thus contributes to the toxicity of aniline, while at a high dose, it is also cardiotoxic, perhaps due to anoxia associated with the marked methemoglobinemia. These results further support the involvement of oxidative stress in the splenotoxicity of aniline which may be caused by its reactive metabolite(s) such as PHA.",
keywords = "Aniline, Lipid peroxidation, Myocardial necrosis, Oxidative stress, Phenylhydroxylamine, Protein oxidation, Spleen",
author = "M Khan and Green, {S. M.} and Ghulam Ansari and Boor, {Paul J.}",
year = "1998",
month = "3",
doi = "10.1006/toxs.1997.2420",
language = "English (US)",
volume = "42",
pages = "64--71",
journal = "Toxicological Sciences",
issn = "1096-6080",
publisher = "Oxford University Press",
number = "1",

}

TY - JOUR

T1 - Phenylhydroxylamine

T2 - Role in aniline-associated splenic oxidative stress and induction of subendocardial necrosis

AU - Khan, M

AU - Green, S. M.

AU - Ansari, Ghulam

AU - Boor, Paul J.

PY - 1998/3

Y1 - 1998/3

N2 - To elucidate the role of N-phenylhydroxylamine (PHA, N-hydroxylated metabolite of aniline) in the selective toxicity of aniline to the spleen, dose-dependent studies were conducted with PHA in rats. Male Sprague-Dawley rats were given four doses each (1 dose/day) of 0.025, 0.05, 0.1, or 0.2 mmol/kg PHA in 0.5 ml of aqueous agar (0.25%) by gavage. The control animals received an equal volume of vehicle only. The animals were euthanized 24 h following the last dose. PHA toxicity in the blood was evident from a dose- dependent increase of methemoglobin. The most affected organ was spleen, which appeared dark and enlarged (splenomegaly) and showed increased spleen- to-body weight ratios, which were 28, 40, 66, and 87% at PHA doses of 0.025, 0.05, 0.1, and 0.2 mmol/kg, respectively. Splenic lipid peroxidation (malondialdehyde content) was higher in all PHA-treated groups, whereas splenic protein oxidation (carbonyl content) increased in only the 0.05, 0.1, and 0.2 mmol/kg groups. The total iron content in the spleen also showed increases of 88, 135, 168, and 209% at PHA doses of 0.025, 0.05, 0.1, and 0.2 mmol/kg, respectively. These biochemical changes were accompanied by a dose- dependent vascular congestion in the spleen, a characteristic feature of aniline toxicity. Although the ratio of organ to body weight increased for both testes and heart at the highest dose, striking morphological changes were observed only in heart. The cardiac lesions consisted of a both acute and resolving multifocal subendocardial necrosis involving predominently the left ventricle. Our results suggest that PHA is a splenotoxin and thus contributes to the toxicity of aniline, while at a high dose, it is also cardiotoxic, perhaps due to anoxia associated with the marked methemoglobinemia. These results further support the involvement of oxidative stress in the splenotoxicity of aniline which may be caused by its reactive metabolite(s) such as PHA.

AB - To elucidate the role of N-phenylhydroxylamine (PHA, N-hydroxylated metabolite of aniline) in the selective toxicity of aniline to the spleen, dose-dependent studies were conducted with PHA in rats. Male Sprague-Dawley rats were given four doses each (1 dose/day) of 0.025, 0.05, 0.1, or 0.2 mmol/kg PHA in 0.5 ml of aqueous agar (0.25%) by gavage. The control animals received an equal volume of vehicle only. The animals were euthanized 24 h following the last dose. PHA toxicity in the blood was evident from a dose- dependent increase of methemoglobin. The most affected organ was spleen, which appeared dark and enlarged (splenomegaly) and showed increased spleen- to-body weight ratios, which were 28, 40, 66, and 87% at PHA doses of 0.025, 0.05, 0.1, and 0.2 mmol/kg, respectively. Splenic lipid peroxidation (malondialdehyde content) was higher in all PHA-treated groups, whereas splenic protein oxidation (carbonyl content) increased in only the 0.05, 0.1, and 0.2 mmol/kg groups. The total iron content in the spleen also showed increases of 88, 135, 168, and 209% at PHA doses of 0.025, 0.05, 0.1, and 0.2 mmol/kg, respectively. These biochemical changes were accompanied by a dose- dependent vascular congestion in the spleen, a characteristic feature of aniline toxicity. Although the ratio of organ to body weight increased for both testes and heart at the highest dose, striking morphological changes were observed only in heart. The cardiac lesions consisted of a both acute and resolving multifocal subendocardial necrosis involving predominently the left ventricle. Our results suggest that PHA is a splenotoxin and thus contributes to the toxicity of aniline, while at a high dose, it is also cardiotoxic, perhaps due to anoxia associated with the marked methemoglobinemia. These results further support the involvement of oxidative stress in the splenotoxicity of aniline which may be caused by its reactive metabolite(s) such as PHA.

KW - Aniline

KW - Lipid peroxidation

KW - Myocardial necrosis

KW - Oxidative stress

KW - Phenylhydroxylamine

KW - Protein oxidation

KW - Spleen

UR - http://www.scopus.com/inward/record.url?scp=0031896296&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031896296&partnerID=8YFLogxK

U2 - 10.1006/toxs.1997.2420

DO - 10.1006/toxs.1997.2420

M3 - Article

VL - 42

SP - 64

EP - 71

JO - Toxicological Sciences

JF - Toxicological Sciences

SN - 1096-6080

IS - 1

ER -