Species variation in toxication and detoxication of acetaminophen in vivo

A comparative study of biliary and urinary excretion of acetaminophen metabolites

Z. Gregus, C. Madhu, C. D. Klaassen

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

Acetaminophen (AA) is converted to a toxic electrophile that may subsequently form a glutathione conjugate (AA-GS). In addition to the toxication pathway metabolites, which consist of AA-GS and its hydrolysis products (AA-cysteinylglycine, AA-cysteine and AA-mercapturate), detoxication pathway metabolites, such as AA-glucuronide and AA-sulfate, are also formed. In order to evaluate the role of these opposing pathways in the reported species variations in susceptibility to AA-induced liver injury, AA was administered to hamsters and mice, species which are susceptible to AA-induced liver injury, and to rats, rabbits and guinea pigs, species which are relatively resistant to AA-induced liver injury, and the biliary and urinary excretion of AA metabolites were measured simultaneously for 2 hr after administration of AA (1 mmol/kg i.v.). The AA-susceptible species excreted 27 to 42% of the dose as toxication pathway metabolites, whereas the resistant species excreted only 5 to 7% of the dose as toxication pathway metabolites. Most of the toxication pathway metabolites appeared in bile, where their composition reflected hepatic γ-glutamyltranspeptidase activity; hamsters and mice (low γ-glutamyltranspeptidase activity) excreted mainly AA-GS, whereas bile from rabbits and guinea pigs (high γ-glutamyltranspeptidase activity) contained significant amounts of AA-GS hydrolysis products. Thus, the biliary excretion of AA-GS hydrolysis products. Thus, the biliary excretion of AA-GS and its hydrolysis products may be used as an index of toxic activation of AA. The excretion of the detoxication pathway metabolites (AA-glucuronide and AA-sulfate) was 74, 62, 41, 27 and 12% of the dose in guinea pigs, rats, mice, rabbits and hamsters respectively. Most of the detoxication pathway metabolites appeared in urine. Half of the detoxication pathway metabolites in rats was AA-sulfate, whereas the other species excreted mainly AA-glucuronide. The ratio of toxication/detoxication pathway metabolites excreted was 2.2, 1.0, 0.25, 0.1 and 0.08 for hamsters, mice, rabbits, rats and guinea pigs, respectively. These ratios are inversely related to the hepatotoxic dose reported for these species, indicating that sensitivity to AA-induced liver necrosis is determined by the balance between toxication and detoxication metabolic pathways.

Original languageEnglish
Pages (from-to)91-99
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume244
Issue number1
Publication statusPublished - 1988

Fingerprint

Acetaminophen
Cricetinae
Guinea Pigs
Hydrolysis
Liver
Rabbits
Poisons
Hepatobiliary Elimination
Bile
Wounds and Injuries
Metabolic Networks and Pathways
Necrosis

ASJC Scopus subject areas

  • Pharmacology

Cite this

@article{619cb66e3d4c4ec886f7ef14a6d25a70,
title = "Species variation in toxication and detoxication of acetaminophen in vivo: A comparative study of biliary and urinary excretion of acetaminophen metabolites",
abstract = "Acetaminophen (AA) is converted to a toxic electrophile that may subsequently form a glutathione conjugate (AA-GS). In addition to the toxication pathway metabolites, which consist of AA-GS and its hydrolysis products (AA-cysteinylglycine, AA-cysteine and AA-mercapturate), detoxication pathway metabolites, such as AA-glucuronide and AA-sulfate, are also formed. In order to evaluate the role of these opposing pathways in the reported species variations in susceptibility to AA-induced liver injury, AA was administered to hamsters and mice, species which are susceptible to AA-induced liver injury, and to rats, rabbits and guinea pigs, species which are relatively resistant to AA-induced liver injury, and the biliary and urinary excretion of AA metabolites were measured simultaneously for 2 hr after administration of AA (1 mmol/kg i.v.). The AA-susceptible species excreted 27 to 42{\%} of the dose as toxication pathway metabolites, whereas the resistant species excreted only 5 to 7{\%} of the dose as toxication pathway metabolites. Most of the toxication pathway metabolites appeared in bile, where their composition reflected hepatic γ-glutamyltranspeptidase activity; hamsters and mice (low γ-glutamyltranspeptidase activity) excreted mainly AA-GS, whereas bile from rabbits and guinea pigs (high γ-glutamyltranspeptidase activity) contained significant amounts of AA-GS hydrolysis products. Thus, the biliary excretion of AA-GS hydrolysis products. Thus, the biliary excretion of AA-GS and its hydrolysis products may be used as an index of toxic activation of AA. The excretion of the detoxication pathway metabolites (AA-glucuronide and AA-sulfate) was 74, 62, 41, 27 and 12{\%} of the dose in guinea pigs, rats, mice, rabbits and hamsters respectively. Most of the detoxication pathway metabolites appeared in urine. Half of the detoxication pathway metabolites in rats was AA-sulfate, whereas the other species excreted mainly AA-glucuronide. The ratio of toxication/detoxication pathway metabolites excreted was 2.2, 1.0, 0.25, 0.1 and 0.08 for hamsters, mice, rabbits, rats and guinea pigs, respectively. These ratios are inversely related to the hepatotoxic dose reported for these species, indicating that sensitivity to AA-induced liver necrosis is determined by the balance between toxication and detoxication metabolic pathways.",
author = "Z. Gregus and C. Madhu and Klaassen, {C. D.}",
year = "1988",
language = "English",
volume = "244",
pages = "91--99",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "1",

}

TY - JOUR

T1 - Species variation in toxication and detoxication of acetaminophen in vivo

T2 - A comparative study of biliary and urinary excretion of acetaminophen metabolites

AU - Gregus, Z.

AU - Madhu, C.

AU - Klaassen, C. D.

PY - 1988

Y1 - 1988

N2 - Acetaminophen (AA) is converted to a toxic electrophile that may subsequently form a glutathione conjugate (AA-GS). In addition to the toxication pathway metabolites, which consist of AA-GS and its hydrolysis products (AA-cysteinylglycine, AA-cysteine and AA-mercapturate), detoxication pathway metabolites, such as AA-glucuronide and AA-sulfate, are also formed. In order to evaluate the role of these opposing pathways in the reported species variations in susceptibility to AA-induced liver injury, AA was administered to hamsters and mice, species which are susceptible to AA-induced liver injury, and to rats, rabbits and guinea pigs, species which are relatively resistant to AA-induced liver injury, and the biliary and urinary excretion of AA metabolites were measured simultaneously for 2 hr after administration of AA (1 mmol/kg i.v.). The AA-susceptible species excreted 27 to 42% of the dose as toxication pathway metabolites, whereas the resistant species excreted only 5 to 7% of the dose as toxication pathway metabolites. Most of the toxication pathway metabolites appeared in bile, where their composition reflected hepatic γ-glutamyltranspeptidase activity; hamsters and mice (low γ-glutamyltranspeptidase activity) excreted mainly AA-GS, whereas bile from rabbits and guinea pigs (high γ-glutamyltranspeptidase activity) contained significant amounts of AA-GS hydrolysis products. Thus, the biliary excretion of AA-GS hydrolysis products. Thus, the biliary excretion of AA-GS and its hydrolysis products may be used as an index of toxic activation of AA. The excretion of the detoxication pathway metabolites (AA-glucuronide and AA-sulfate) was 74, 62, 41, 27 and 12% of the dose in guinea pigs, rats, mice, rabbits and hamsters respectively. Most of the detoxication pathway metabolites appeared in urine. Half of the detoxication pathway metabolites in rats was AA-sulfate, whereas the other species excreted mainly AA-glucuronide. The ratio of toxication/detoxication pathway metabolites excreted was 2.2, 1.0, 0.25, 0.1 and 0.08 for hamsters, mice, rabbits, rats and guinea pigs, respectively. These ratios are inversely related to the hepatotoxic dose reported for these species, indicating that sensitivity to AA-induced liver necrosis is determined by the balance between toxication and detoxication metabolic pathways.

AB - Acetaminophen (AA) is converted to a toxic electrophile that may subsequently form a glutathione conjugate (AA-GS). In addition to the toxication pathway metabolites, which consist of AA-GS and its hydrolysis products (AA-cysteinylglycine, AA-cysteine and AA-mercapturate), detoxication pathway metabolites, such as AA-glucuronide and AA-sulfate, are also formed. In order to evaluate the role of these opposing pathways in the reported species variations in susceptibility to AA-induced liver injury, AA was administered to hamsters and mice, species which are susceptible to AA-induced liver injury, and to rats, rabbits and guinea pigs, species which are relatively resistant to AA-induced liver injury, and the biliary and urinary excretion of AA metabolites were measured simultaneously for 2 hr after administration of AA (1 mmol/kg i.v.). The AA-susceptible species excreted 27 to 42% of the dose as toxication pathway metabolites, whereas the resistant species excreted only 5 to 7% of the dose as toxication pathway metabolites. Most of the toxication pathway metabolites appeared in bile, where their composition reflected hepatic γ-glutamyltranspeptidase activity; hamsters and mice (low γ-glutamyltranspeptidase activity) excreted mainly AA-GS, whereas bile from rabbits and guinea pigs (high γ-glutamyltranspeptidase activity) contained significant amounts of AA-GS hydrolysis products. Thus, the biliary excretion of AA-GS hydrolysis products. Thus, the biliary excretion of AA-GS and its hydrolysis products may be used as an index of toxic activation of AA. The excretion of the detoxication pathway metabolites (AA-glucuronide and AA-sulfate) was 74, 62, 41, 27 and 12% of the dose in guinea pigs, rats, mice, rabbits and hamsters respectively. Most of the detoxication pathway metabolites appeared in urine. Half of the detoxication pathway metabolites in rats was AA-sulfate, whereas the other species excreted mainly AA-glucuronide. The ratio of toxication/detoxication pathway metabolites excreted was 2.2, 1.0, 0.25, 0.1 and 0.08 for hamsters, mice, rabbits, rats and guinea pigs, respectively. These ratios are inversely related to the hepatotoxic dose reported for these species, indicating that sensitivity to AA-induced liver necrosis is determined by the balance between toxication and detoxication metabolic pathways.

UR - http://www.scopus.com/inward/record.url?scp=0023877502&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0023877502&partnerID=8YFLogxK

M3 - Article

VL - 244

SP - 91

EP - 99

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 1

ER -