Hepatoprotection by dimethyl sulfoxide

III. Role of inhibition of the bioactivation and covalent binding of chloroform

R. C. Lind, C. K. Begay, A Jay Gandolfi

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Dimethyl sulfoxide (DMSO) has previously been shown to have the ability to attenuate chloroform (CHCl3)-induced liver injury in the naive rat even when administered 24 h after the toxicant. These studies were undertaken to determine if the protective action by late administration of DMSO is due to an inhibition of the bioactivation of CHCl3. This was done by comparing the cytochrome P450 inhibitors, diallyl sulfide (DAS), and aminobenzotriazole (ABT) to DMSO for their protective efficacy when administered 24 h after CHCl3 exposure. In addition, 14CHCl3 was utilized to measure the effect of DMSO and ABT on the covalent binding of CHCl3 in the liver following their late administration. Male Sprague-Dawley rats (300-350 g) received 0.75 ml/kg CHCl3 po. Twenty-four hours later, they received ip injection of 2 ml/kg DMSO, 100 mg/kg DAS, or 30 mg/kg ABT. Plasma ALT activities and quantitation of liver injury by light microscopy at 48 h after CHCl3 dosing indicated that all three treatments were equally effective at protecting the liver. A detailed study of the time course of injury development indicated that the protective action of DMSO was occurring within 10 h of its administration. Therefore, in the radiolabel studies, rats were killed 24-34 h after receiving 0.75 ml/kg CHCl3 μCi/kg 14CHCl3) po. Treatment with ABT at 24 h after 14CHCl3 dosing decreased the covalent binding of 14C to hepatic protein by 35% and reduced the amount of 14C in the blood by 50% by 10 h after its administration. DMSO treatment did not significantly affect any of these parameters. The lack of effect by late administration of DMSO on the covalent binding of CHCl3 would indicate that DMSO may offer protection by mechanisms other than inhibition of the bioactivation of CHCl3. These studies also indicate that specific cytochrome P450 inhibitors may be of benefit in clinical situations to help treat the delayed onset hepatitis that can result following poisoning with an organohalogen, even if the antidotes are administered a number of hours after the initial exposure. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)145-150
Number of pages6
JournalToxicology and Applied Pharmacology
Volume166
Issue number2
DOIs
StatePublished - Jul 15 2000

Fingerprint

Chloroform
Dimethyl Sulfoxide
Liver
Rats
Cytochrome P-450 Enzyme System
Wounds and Injuries
Antidotes
Poisoning
Hepatitis
Optical microscopy
Sprague Dawley Rats
Microscopy
Blood
Therapeutics
Plasmas
Light
Injections

Keywords

  • Aminobenzotriazole
  • Antidote
  • Chloroform
  • Covalent binding
  • Diallyl sulfide
  • Dimethyl sulfoxide
  • Liver injury
  • Rat

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Hepatoprotection by dimethyl sulfoxide : III. Role of inhibition of the bioactivation and covalent binding of chloroform. / Lind, R. C.; Begay, C. K.; Gandolfi, A Jay.

In: Toxicology and Applied Pharmacology, Vol. 166, No. 2, 15.07.2000, p. 145-150.

Research output: Contribution to journalArticle

@article{e01bb4f1e83e49cd81eaa5001c5b5306,
title = "Hepatoprotection by dimethyl sulfoxide: III. Role of inhibition of the bioactivation and covalent binding of chloroform",
abstract = "Dimethyl sulfoxide (DMSO) has previously been shown to have the ability to attenuate chloroform (CHCl3)-induced liver injury in the naive rat even when administered 24 h after the toxicant. These studies were undertaken to determine if the protective action by late administration of DMSO is due to an inhibition of the bioactivation of CHCl3. This was done by comparing the cytochrome P450 inhibitors, diallyl sulfide (DAS), and aminobenzotriazole (ABT) to DMSO for their protective efficacy when administered 24 h after CHCl3 exposure. In addition, 14CHCl3 was utilized to measure the effect of DMSO and ABT on the covalent binding of CHCl3 in the liver following their late administration. Male Sprague-Dawley rats (300-350 g) received 0.75 ml/kg CHCl3 po. Twenty-four hours later, they received ip injection of 2 ml/kg DMSO, 100 mg/kg DAS, or 30 mg/kg ABT. Plasma ALT activities and quantitation of liver injury by light microscopy at 48 h after CHCl3 dosing indicated that all three treatments were equally effective at protecting the liver. A detailed study of the time course of injury development indicated that the protective action of DMSO was occurring within 10 h of its administration. Therefore, in the radiolabel studies, rats were killed 24-34 h after receiving 0.75 ml/kg CHCl3 μCi/kg 14CHCl3) po. Treatment with ABT at 24 h after 14CHCl3 dosing decreased the covalent binding of 14C to hepatic protein by 35{\%} and reduced the amount of 14C in the blood by 50{\%} by 10 h after its administration. DMSO treatment did not significantly affect any of these parameters. The lack of effect by late administration of DMSO on the covalent binding of CHCl3 would indicate that DMSO may offer protection by mechanisms other than inhibition of the bioactivation of CHCl3. These studies also indicate that specific cytochrome P450 inhibitors may be of benefit in clinical situations to help treat the delayed onset hepatitis that can result following poisoning with an organohalogen, even if the antidotes are administered a number of hours after the initial exposure. (C) 2000 Academic Press.",
keywords = "Aminobenzotriazole, Antidote, Chloroform, Covalent binding, Diallyl sulfide, Dimethyl sulfoxide, Liver injury, Rat",
author = "Lind, {R. C.} and Begay, {C. K.} and Gandolfi, {A Jay}",
year = "2000",
month = "7",
day = "15",
doi = "10.1006/taap.2000.8949",
language = "English (US)",
volume = "166",
pages = "145--150",
journal = "Toxicology and Applied Pharmacology",
issn = "0041-008X",
publisher = "Academic Press Inc.",
number = "2",

}

TY - JOUR

T1 - Hepatoprotection by dimethyl sulfoxide

T2 - III. Role of inhibition of the bioactivation and covalent binding of chloroform

AU - Lind, R. C.

AU - Begay, C. K.

AU - Gandolfi, A Jay

PY - 2000/7/15

Y1 - 2000/7/15

N2 - Dimethyl sulfoxide (DMSO) has previously been shown to have the ability to attenuate chloroform (CHCl3)-induced liver injury in the naive rat even when administered 24 h after the toxicant. These studies were undertaken to determine if the protective action by late administration of DMSO is due to an inhibition of the bioactivation of CHCl3. This was done by comparing the cytochrome P450 inhibitors, diallyl sulfide (DAS), and aminobenzotriazole (ABT) to DMSO for their protective efficacy when administered 24 h after CHCl3 exposure. In addition, 14CHCl3 was utilized to measure the effect of DMSO and ABT on the covalent binding of CHCl3 in the liver following their late administration. Male Sprague-Dawley rats (300-350 g) received 0.75 ml/kg CHCl3 po. Twenty-four hours later, they received ip injection of 2 ml/kg DMSO, 100 mg/kg DAS, or 30 mg/kg ABT. Plasma ALT activities and quantitation of liver injury by light microscopy at 48 h after CHCl3 dosing indicated that all three treatments were equally effective at protecting the liver. A detailed study of the time course of injury development indicated that the protective action of DMSO was occurring within 10 h of its administration. Therefore, in the radiolabel studies, rats were killed 24-34 h after receiving 0.75 ml/kg CHCl3 μCi/kg 14CHCl3) po. Treatment with ABT at 24 h after 14CHCl3 dosing decreased the covalent binding of 14C to hepatic protein by 35% and reduced the amount of 14C in the blood by 50% by 10 h after its administration. DMSO treatment did not significantly affect any of these parameters. The lack of effect by late administration of DMSO on the covalent binding of CHCl3 would indicate that DMSO may offer protection by mechanisms other than inhibition of the bioactivation of CHCl3. These studies also indicate that specific cytochrome P450 inhibitors may be of benefit in clinical situations to help treat the delayed onset hepatitis that can result following poisoning with an organohalogen, even if the antidotes are administered a number of hours after the initial exposure. (C) 2000 Academic Press.

AB - Dimethyl sulfoxide (DMSO) has previously been shown to have the ability to attenuate chloroform (CHCl3)-induced liver injury in the naive rat even when administered 24 h after the toxicant. These studies were undertaken to determine if the protective action by late administration of DMSO is due to an inhibition of the bioactivation of CHCl3. This was done by comparing the cytochrome P450 inhibitors, diallyl sulfide (DAS), and aminobenzotriazole (ABT) to DMSO for their protective efficacy when administered 24 h after CHCl3 exposure. In addition, 14CHCl3 was utilized to measure the effect of DMSO and ABT on the covalent binding of CHCl3 in the liver following their late administration. Male Sprague-Dawley rats (300-350 g) received 0.75 ml/kg CHCl3 po. Twenty-four hours later, they received ip injection of 2 ml/kg DMSO, 100 mg/kg DAS, or 30 mg/kg ABT. Plasma ALT activities and quantitation of liver injury by light microscopy at 48 h after CHCl3 dosing indicated that all three treatments were equally effective at protecting the liver. A detailed study of the time course of injury development indicated that the protective action of DMSO was occurring within 10 h of its administration. Therefore, in the radiolabel studies, rats were killed 24-34 h after receiving 0.75 ml/kg CHCl3 μCi/kg 14CHCl3) po. Treatment with ABT at 24 h after 14CHCl3 dosing decreased the covalent binding of 14C to hepatic protein by 35% and reduced the amount of 14C in the blood by 50% by 10 h after its administration. DMSO treatment did not significantly affect any of these parameters. The lack of effect by late administration of DMSO on the covalent binding of CHCl3 would indicate that DMSO may offer protection by mechanisms other than inhibition of the bioactivation of CHCl3. These studies also indicate that specific cytochrome P450 inhibitors may be of benefit in clinical situations to help treat the delayed onset hepatitis that can result following poisoning with an organohalogen, even if the antidotes are administered a number of hours after the initial exposure. (C) 2000 Academic Press.

KW - Aminobenzotriazole

KW - Antidote

KW - Chloroform

KW - Covalent binding

KW - Diallyl sulfide

KW - Dimethyl sulfoxide

KW - Liver injury

KW - Rat

UR - http://www.scopus.com/inward/record.url?scp=0034661455&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034661455&partnerID=8YFLogxK

U2 - 10.1006/taap.2000.8949

DO - 10.1006/taap.2000.8949

M3 - Article

VL - 166

SP - 145

EP - 150

JO - Toxicology and Applied Pharmacology

JF - Toxicology and Applied Pharmacology

SN - 0041-008X

IS - 2

ER -