Mitigation of nitrofurantoin-induced toxicity in the perfused rat lung

Craig E. Bernard, Amani Magid, T. S.Benedict Yen, Betty Ann Hoener

Research output: Contribution to journalArticle

Abstract

1 Nitrofurantoin is an antimicrobial agent which produces pulmonary toxicity via the redox cycling of the nitro group and its radical anion. This futile cycling triggers a complex series of events known collectively as oxidative stress. 2 In the isolated perfused rat lung, nitrofurantoin induced a decrease in tissue levels of glutathione but not protein thiols by the end of the 180 min experiment. There was no decline in tissue levels of angiotensin converting enzyme (a marker of cell disruption). However, edema was extensive as monitored in real time by weight gain (2.71 ± 0.56 g vs 0.63 ± 0.53 g in control, P<0.05, n=4) and lung mechanical functioning. The edema was matched by an increase in lavage proteins (85 ± 15 mg vs 16 ± 9 mg in controls, P<0.05, n=4). Electron microscopic examination of tissue indicated that the endothelial cells were detached from the basement membrane which would account for the edema. 3 Co-infusion of penicillamine, N-acetylcysteine or N-(2-mercaptopropionyl)-glycine which can protect tissue from oxidative stress failed to mitigate NFT-induced edema. Allopurinol, an inhibitor of xanthine oxidase and a metal chelator, significantly decreased weight gain but did not prevent the loss of glutathione. These results suggested that allopurinol was not blocking metabolic activation of NFT by xanthine oxidase but scavenging metal cations which can initiate and/or propagate the oxidative stress cascade. 4 We concluded that, in the isolated perfused rat lung, the classic pathway of oxidative stress induced by NFT is interrupted at the stage of GSH loss. These experiments demonstrated that organ function was compromised more than the individual cells. They also suggested that allopurinol may prove beneficial in modulating NFT pulmonary toxicity.

Original languageEnglish (US)
Pages (from-to)727-732
Number of pages6
JournalHuman and Experimental Toxicology
Volume16
Issue number12
DOIs
StatePublished - Jan 1 1997

Fingerprint

Nitrofurantoin
Oxidative stress
Allopurinol
Toxicity
Rats
Tissue
Edema
Oxidative Stress
Lung
Xanthine Oxidase
Glutathione
Metals
Weight Gain
Substrate Cycling
Penicillamine
Scavenging
Endothelial cells
Acetylcysteine
Peptidyl-Dipeptidase A
Chelating Agents

Keywords

  • Glutathione
  • Nitrofurantoin
  • Oxidative stress
  • Pulminary toxicity

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Mitigation of nitrofurantoin-induced toxicity in the perfused rat lung. / Bernard, Craig E.; Magid, Amani; Yen, T. S.Benedict; Hoener, Betty Ann.

In: Human and Experimental Toxicology, Vol. 16, No. 12, 01.01.1997, p. 727-732.

Research output: Contribution to journalArticle

Bernard, Craig E. ; Magid, Amani ; Yen, T. S.Benedict ; Hoener, Betty Ann. / Mitigation of nitrofurantoin-induced toxicity in the perfused rat lung. In: Human and Experimental Toxicology. 1997 ; Vol. 16, No. 12. pp. 727-732.
@article{aebc322fb31e4399be63711cd51eee61,
title = "Mitigation of nitrofurantoin-induced toxicity in the perfused rat lung",
abstract = "1 Nitrofurantoin is an antimicrobial agent which produces pulmonary toxicity via the redox cycling of the nitro group and its radical anion. This futile cycling triggers a complex series of events known collectively as oxidative stress. 2 In the isolated perfused rat lung, nitrofurantoin induced a decrease in tissue levels of glutathione but not protein thiols by the end of the 180 min experiment. There was no decline in tissue levels of angiotensin converting enzyme (a marker of cell disruption). However, edema was extensive as monitored in real time by weight gain (2.71 ± 0.56 g vs 0.63 ± 0.53 g in control, P<0.05, n=4) and lung mechanical functioning. The edema was matched by an increase in lavage proteins (85 ± 15 mg vs 16 ± 9 mg in controls, P<0.05, n=4). Electron microscopic examination of tissue indicated that the endothelial cells were detached from the basement membrane which would account for the edema. 3 Co-infusion of penicillamine, N-acetylcysteine or N-(2-mercaptopropionyl)-glycine which can protect tissue from oxidative stress failed to mitigate NFT-induced edema. Allopurinol, an inhibitor of xanthine oxidase and a metal chelator, significantly decreased weight gain but did not prevent the loss of glutathione. These results suggested that allopurinol was not blocking metabolic activation of NFT by xanthine oxidase but scavenging metal cations which can initiate and/or propagate the oxidative stress cascade. 4 We concluded that, in the isolated perfused rat lung, the classic pathway of oxidative stress induced by NFT is interrupted at the stage of GSH loss. These experiments demonstrated that organ function was compromised more than the individual cells. They also suggested that allopurinol may prove beneficial in modulating NFT pulmonary toxicity.",
keywords = "Glutathione, Nitrofurantoin, Oxidative stress, Pulminary toxicity",
author = "Bernard, {Craig E.} and Amani Magid and Yen, {T. S.Benedict} and Hoener, {Betty Ann}",
year = "1997",
month = "1",
day = "1",
doi = "10.1177/096032719701601206",
language = "English (US)",
volume = "16",
pages = "727--732",
journal = "Human and Experimental Toxicology",
issn = "0960-3271",
publisher = "SAGE Publications Inc.",
number = "12",

}

TY - JOUR

T1 - Mitigation of nitrofurantoin-induced toxicity in the perfused rat lung

AU - Bernard, Craig E.

AU - Magid, Amani

AU - Yen, T. S.Benedict

AU - Hoener, Betty Ann

PY - 1997/1/1

Y1 - 1997/1/1

N2 - 1 Nitrofurantoin is an antimicrobial agent which produces pulmonary toxicity via the redox cycling of the nitro group and its radical anion. This futile cycling triggers a complex series of events known collectively as oxidative stress. 2 In the isolated perfused rat lung, nitrofurantoin induced a decrease in tissue levels of glutathione but not protein thiols by the end of the 180 min experiment. There was no decline in tissue levels of angiotensin converting enzyme (a marker of cell disruption). However, edema was extensive as monitored in real time by weight gain (2.71 ± 0.56 g vs 0.63 ± 0.53 g in control, P<0.05, n=4) and lung mechanical functioning. The edema was matched by an increase in lavage proteins (85 ± 15 mg vs 16 ± 9 mg in controls, P<0.05, n=4). Electron microscopic examination of tissue indicated that the endothelial cells were detached from the basement membrane which would account for the edema. 3 Co-infusion of penicillamine, N-acetylcysteine or N-(2-mercaptopropionyl)-glycine which can protect tissue from oxidative stress failed to mitigate NFT-induced edema. Allopurinol, an inhibitor of xanthine oxidase and a metal chelator, significantly decreased weight gain but did not prevent the loss of glutathione. These results suggested that allopurinol was not blocking metabolic activation of NFT by xanthine oxidase but scavenging metal cations which can initiate and/or propagate the oxidative stress cascade. 4 We concluded that, in the isolated perfused rat lung, the classic pathway of oxidative stress induced by NFT is interrupted at the stage of GSH loss. These experiments demonstrated that organ function was compromised more than the individual cells. They also suggested that allopurinol may prove beneficial in modulating NFT pulmonary toxicity.

AB - 1 Nitrofurantoin is an antimicrobial agent which produces pulmonary toxicity via the redox cycling of the nitro group and its radical anion. This futile cycling triggers a complex series of events known collectively as oxidative stress. 2 In the isolated perfused rat lung, nitrofurantoin induced a decrease in tissue levels of glutathione but not protein thiols by the end of the 180 min experiment. There was no decline in tissue levels of angiotensin converting enzyme (a marker of cell disruption). However, edema was extensive as monitored in real time by weight gain (2.71 ± 0.56 g vs 0.63 ± 0.53 g in control, P<0.05, n=4) and lung mechanical functioning. The edema was matched by an increase in lavage proteins (85 ± 15 mg vs 16 ± 9 mg in controls, P<0.05, n=4). Electron microscopic examination of tissue indicated that the endothelial cells were detached from the basement membrane which would account for the edema. 3 Co-infusion of penicillamine, N-acetylcysteine or N-(2-mercaptopropionyl)-glycine which can protect tissue from oxidative stress failed to mitigate NFT-induced edema. Allopurinol, an inhibitor of xanthine oxidase and a metal chelator, significantly decreased weight gain but did not prevent the loss of glutathione. These results suggested that allopurinol was not blocking metabolic activation of NFT by xanthine oxidase but scavenging metal cations which can initiate and/or propagate the oxidative stress cascade. 4 We concluded that, in the isolated perfused rat lung, the classic pathway of oxidative stress induced by NFT is interrupted at the stage of GSH loss. These experiments demonstrated that organ function was compromised more than the individual cells. They also suggested that allopurinol may prove beneficial in modulating NFT pulmonary toxicity.

KW - Glutathione

KW - Nitrofurantoin

KW - Oxidative stress

KW - Pulminary toxicity

UR - http://www.scopus.com/inward/record.url?scp=0031442193&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031442193&partnerID=8YFLogxK

U2 - 10.1177/096032719701601206

DO - 10.1177/096032719701601206

M3 - Article

VL - 16

SP - 727

EP - 732

JO - Human and Experimental Toxicology

JF - Human and Experimental Toxicology

SN - 0960-3271

IS - 12

ER -