Isoniazid hepatotoxicity: The relationship between covalent binding and metabolism in vivo

J. A. Timbrell, J. R. Mitchell, W. R. Snodgrass, S. D. Nelson

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

The relationship between the hepatotoxicity and metabolism of isoniazid and its metabolites, acetylisoniazed and acetylhydrazine, has been investigated. Toxic doses of acetylisoniazid and acetylhydrazine, radiolabeled in the acetyl group, were found to bind covalently to liver protein in vivo. This binding was mediated by the microsomal enzyme system as indicated by the effects of pretreatments altering the activity of these enzymes. Metabolic studies revealed that the pretreatment increased the metabolism of the acetylhydrazine moiety of acetyl-labeled acetylisoniazed and of acetylhydrazine itself by the microsomal enzyme system. Pretreatment with the acyl amidase inhibitor, bis-p-nitrophenyl phosphate, inhibited the hydrolysis of acetylisoniazed to isonicotinic acid plus acetylhydrazine and concomitantly decreased the covalent binding of acetyl-labeled acetylisoniazid. the changes in the metabolism of isoniazid, acetylisoniazid changes in acetylhydrazine effected by various pretreatments paralleled changesin the severity of the hepatic necrosis caused by the compounds. These results strongly suggest that acetylhydrazine is the metabolite responsible for the hepatic necrosis caused by isoniazid and that microsomal metabolism of acetylhydrazine in vivo leads to the production of a reactive acylating species capable of reacting covalently with tissue macromolecules.

Original languageEnglish (US)
Pages (from-to)364-369
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume213
Issue number2
StatePublished - 1980
Externally publishedYes

Fingerprint

Isoniazid
amidase
Liver
Isonicotinic Acids
Necrosis
Enzymes
acetylhydrazine
Poisons
Hydrolysis

ASJC Scopus subject areas

  • Pharmacology

Cite this

Timbrell, J. A., Mitchell, J. R., Snodgrass, W. R., & Nelson, S. D. (1980). Isoniazid hepatotoxicity: The relationship between covalent binding and metabolism in vivo. Journal of Pharmacology and Experimental Therapeutics, 213(2), 364-369.

Isoniazid hepatotoxicity : The relationship between covalent binding and metabolism in vivo. / Timbrell, J. A.; Mitchell, J. R.; Snodgrass, W. R.; Nelson, S. D.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 213, No. 2, 1980, p. 364-369.

Research output: Contribution to journalArticle

Timbrell, JA, Mitchell, JR, Snodgrass, WR & Nelson, SD 1980, 'Isoniazid hepatotoxicity: The relationship between covalent binding and metabolism in vivo', Journal of Pharmacology and Experimental Therapeutics, vol. 213, no. 2, pp. 364-369.
Timbrell, J. A. ; Mitchell, J. R. ; Snodgrass, W. R. ; Nelson, S. D. / Isoniazid hepatotoxicity : The relationship between covalent binding and metabolism in vivo. In: Journal of Pharmacology and Experimental Therapeutics. 1980 ; Vol. 213, No. 2. pp. 364-369.
@article{33c32a9f260543aaa4fea2eb34ddc6c6,
title = "Isoniazid hepatotoxicity: The relationship between covalent binding and metabolism in vivo",
abstract = "The relationship between the hepatotoxicity and metabolism of isoniazid and its metabolites, acetylisoniazed and acetylhydrazine, has been investigated. Toxic doses of acetylisoniazid and acetylhydrazine, radiolabeled in the acetyl group, were found to bind covalently to liver protein in vivo. This binding was mediated by the microsomal enzyme system as indicated by the effects of pretreatments altering the activity of these enzymes. Metabolic studies revealed that the pretreatment increased the metabolism of the acetylhydrazine moiety of acetyl-labeled acetylisoniazed and of acetylhydrazine itself by the microsomal enzyme system. Pretreatment with the acyl amidase inhibitor, bis-p-nitrophenyl phosphate, inhibited the hydrolysis of acetylisoniazed to isonicotinic acid plus acetylhydrazine and concomitantly decreased the covalent binding of acetyl-labeled acetylisoniazid. the changes in the metabolism of isoniazid, acetylisoniazid changes in acetylhydrazine effected by various pretreatments paralleled changesin the severity of the hepatic necrosis caused by the compounds. These results strongly suggest that acetylhydrazine is the metabolite responsible for the hepatic necrosis caused by isoniazid and that microsomal metabolism of acetylhydrazine in vivo leads to the production of a reactive acylating species capable of reacting covalently with tissue macromolecules.",
author = "Timbrell, {J. A.} and Mitchell, {J. R.} and Snodgrass, {W. R.} and Nelson, {S. D.}",
year = "1980",
language = "English (US)",
volume = "213",
pages = "364--369",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

TY - JOUR

T1 - Isoniazid hepatotoxicity

T2 - The relationship between covalent binding and metabolism in vivo

AU - Timbrell, J. A.

AU - Mitchell, J. R.

AU - Snodgrass, W. R.

AU - Nelson, S. D.

PY - 1980

Y1 - 1980

N2 - The relationship between the hepatotoxicity and metabolism of isoniazid and its metabolites, acetylisoniazed and acetylhydrazine, has been investigated. Toxic doses of acetylisoniazid and acetylhydrazine, radiolabeled in the acetyl group, were found to bind covalently to liver protein in vivo. This binding was mediated by the microsomal enzyme system as indicated by the effects of pretreatments altering the activity of these enzymes. Metabolic studies revealed that the pretreatment increased the metabolism of the acetylhydrazine moiety of acetyl-labeled acetylisoniazed and of acetylhydrazine itself by the microsomal enzyme system. Pretreatment with the acyl amidase inhibitor, bis-p-nitrophenyl phosphate, inhibited the hydrolysis of acetylisoniazed to isonicotinic acid plus acetylhydrazine and concomitantly decreased the covalent binding of acetyl-labeled acetylisoniazid. the changes in the metabolism of isoniazid, acetylisoniazid changes in acetylhydrazine effected by various pretreatments paralleled changesin the severity of the hepatic necrosis caused by the compounds. These results strongly suggest that acetylhydrazine is the metabolite responsible for the hepatic necrosis caused by isoniazid and that microsomal metabolism of acetylhydrazine in vivo leads to the production of a reactive acylating species capable of reacting covalently with tissue macromolecules.

AB - The relationship between the hepatotoxicity and metabolism of isoniazid and its metabolites, acetylisoniazed and acetylhydrazine, has been investigated. Toxic doses of acetylisoniazid and acetylhydrazine, radiolabeled in the acetyl group, were found to bind covalently to liver protein in vivo. This binding was mediated by the microsomal enzyme system as indicated by the effects of pretreatments altering the activity of these enzymes. Metabolic studies revealed that the pretreatment increased the metabolism of the acetylhydrazine moiety of acetyl-labeled acetylisoniazed and of acetylhydrazine itself by the microsomal enzyme system. Pretreatment with the acyl amidase inhibitor, bis-p-nitrophenyl phosphate, inhibited the hydrolysis of acetylisoniazed to isonicotinic acid plus acetylhydrazine and concomitantly decreased the covalent binding of acetyl-labeled acetylisoniazid. the changes in the metabolism of isoniazid, acetylisoniazid changes in acetylhydrazine effected by various pretreatments paralleled changesin the severity of the hepatic necrosis caused by the compounds. These results strongly suggest that acetylhydrazine is the metabolite responsible for the hepatic necrosis caused by isoniazid and that microsomal metabolism of acetylhydrazine in vivo leads to the production of a reactive acylating species capable of reacting covalently with tissue macromolecules.

UR - http://www.scopus.com/inward/record.url?scp=0018909078&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0018909078&partnerID=8YFLogxK

M3 - Article

C2 - 6767840

AN - SCOPUS:0018909078

VL - 213

SP - 364

EP - 369

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 2

ER -