The formation of diglutathionyl dithiocarbonate as a metabolite of chloroform, bromotrichloromethane, and carbon tetrachloride

L. R. Pohl, R. V. Branchflower, R. J. Highet, J. L. Martin, D. S. Nunn, Terrence Monks, J. W. George, J. A. Hinson

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

One hour after the intraperitoneal administration of CHCl 3, CBrCl 3, or CCl 4 to phenobarbital (PB)-treated rats, hepatic GSH levels decreased to 30, 59, and 88% of control levels, respectively; after 4 hr, the GSH levels had returned to 46, 65, 99%, respectively, of control levels. When incubated for 15 min in air with rat liver microsomes from PB-treated rats, a NADPH-generating system, and GSH (5 mM), all of the compounds were converted to diglutathionyl dithiocarbonate (GSCOSG). The rate of conversion of CHCl 3, CBrCl 3, and CCl 4 to GSCOSG was 180, 58, and 8 nmol per mg of protein per 15 min, respectively. The GSCOSG was also identified in bile by 13C-NMR spectroscopy and HPLC as an in vivo metabolite of CHCl 3, CBrCl 3, and CCl 4. After the administration of CHCl 3, CBrCl 3, and CCl 4, 2.89, 0.64, or 0.11 μmol of GSCOSG, respectively, was excreted in 6 hr. These results suggest that CHCl 3, CBrCl 3, and CCl 4 are metabolized in vitro and in vivo to phosgene (COCl 2), which reacts with GSH to produce GSCOSG. The reaction of GSH with COCl 2 may be responsible at least in part for the GSH-depleting properties of CHCL 3, CBrCl 3, and CCl 4, inasmuch as the relative amounts of formation of GSCOSG in vitro and in vivo paralleled their relative GSH-depleting activities.

Original languageEnglish (US)
Pages (from-to)334-339
Number of pages6
JournalDrug Metabolism and Disposition
Volume9
Issue number4
StatePublished - 1981
Externally publishedYes

Fingerprint

Bromotrichloromethane
Carbon Tetrachloride
Chloroform
Metabolites
Rats
Level control
Phenobarbital
Phosgene
Liver Microsomes
diglutathionyl dithiocarbonate
NADP
Bile
Liver
Nuclear magnetic resonance spectroscopy
Magnetic Resonance Spectroscopy
Air
High Pressure Liquid Chromatography

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Pohl, L. R., Branchflower, R. V., Highet, R. J., Martin, J. L., Nunn, D. S., Monks, T., ... Hinson, J. A. (1981). The formation of diglutathionyl dithiocarbonate as a metabolite of chloroform, bromotrichloromethane, and carbon tetrachloride. Drug Metabolism and Disposition, 9(4), 334-339.

The formation of diglutathionyl dithiocarbonate as a metabolite of chloroform, bromotrichloromethane, and carbon tetrachloride. / Pohl, L. R.; Branchflower, R. V.; Highet, R. J.; Martin, J. L.; Nunn, D. S.; Monks, Terrence; George, J. W.; Hinson, J. A.

In: Drug Metabolism and Disposition, Vol. 9, No. 4, 1981, p. 334-339.

Research output: Contribution to journalArticle

Pohl, LR, Branchflower, RV, Highet, RJ, Martin, JL, Nunn, DS, Monks, T, George, JW & Hinson, JA 1981, 'The formation of diglutathionyl dithiocarbonate as a metabolite of chloroform, bromotrichloromethane, and carbon tetrachloride', Drug Metabolism and Disposition, vol. 9, no. 4, pp. 334-339.
Pohl, L. R. ; Branchflower, R. V. ; Highet, R. J. ; Martin, J. L. ; Nunn, D. S. ; Monks, Terrence ; George, J. W. ; Hinson, J. A. / The formation of diglutathionyl dithiocarbonate as a metabolite of chloroform, bromotrichloromethane, and carbon tetrachloride. In: Drug Metabolism and Disposition. 1981 ; Vol. 9, No. 4. pp. 334-339.
@article{d918fe75549b49f38d59e3d3bb984293,
title = "The formation of diglutathionyl dithiocarbonate as a metabolite of chloroform, bromotrichloromethane, and carbon tetrachloride",
abstract = "One hour after the intraperitoneal administration of CHCl 3, CBrCl 3, or CCl 4 to phenobarbital (PB)-treated rats, hepatic GSH levels decreased to 30, 59, and 88{\%} of control levels, respectively; after 4 hr, the GSH levels had returned to 46, 65, 99{\%}, respectively, of control levels. When incubated for 15 min in air with rat liver microsomes from PB-treated rats, a NADPH-generating system, and GSH (5 mM), all of the compounds were converted to diglutathionyl dithiocarbonate (GSCOSG). The rate of conversion of CHCl 3, CBrCl 3, and CCl 4 to GSCOSG was 180, 58, and 8 nmol per mg of protein per 15 min, respectively. The GSCOSG was also identified in bile by 13C-NMR spectroscopy and HPLC as an in vivo metabolite of CHCl 3, CBrCl 3, and CCl 4. After the administration of CHCl 3, CBrCl 3, and CCl 4, 2.89, 0.64, or 0.11 μmol of GSCOSG, respectively, was excreted in 6 hr. These results suggest that CHCl 3, CBrCl 3, and CCl 4 are metabolized in vitro and in vivo to phosgene (COCl 2), which reacts with GSH to produce GSCOSG. The reaction of GSH with COCl 2 may be responsible at least in part for the GSH-depleting properties of CHCL 3, CBrCl 3, and CCl 4, inasmuch as the relative amounts of formation of GSCOSG in vitro and in vivo paralleled their relative GSH-depleting activities.",
author = "Pohl, {L. R.} and Branchflower, {R. V.} and Highet, {R. J.} and Martin, {J. L.} and Nunn, {D. S.} and Terrence Monks and George, {J. W.} and Hinson, {J. A.}",
year = "1981",
language = "English (US)",
volume = "9",
pages = "334--339",
journal = "Drug Metabolism and Disposition",
issn = "0090-9556",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "4",

}

TY - JOUR

T1 - The formation of diglutathionyl dithiocarbonate as a metabolite of chloroform, bromotrichloromethane, and carbon tetrachloride

AU - Pohl, L. R.

AU - Branchflower, R. V.

AU - Highet, R. J.

AU - Martin, J. L.

AU - Nunn, D. S.

AU - Monks, Terrence

AU - George, J. W.

AU - Hinson, J. A.

PY - 1981

Y1 - 1981

N2 - One hour after the intraperitoneal administration of CHCl 3, CBrCl 3, or CCl 4 to phenobarbital (PB)-treated rats, hepatic GSH levels decreased to 30, 59, and 88% of control levels, respectively; after 4 hr, the GSH levels had returned to 46, 65, 99%, respectively, of control levels. When incubated for 15 min in air with rat liver microsomes from PB-treated rats, a NADPH-generating system, and GSH (5 mM), all of the compounds were converted to diglutathionyl dithiocarbonate (GSCOSG). The rate of conversion of CHCl 3, CBrCl 3, and CCl 4 to GSCOSG was 180, 58, and 8 nmol per mg of protein per 15 min, respectively. The GSCOSG was also identified in bile by 13C-NMR spectroscopy and HPLC as an in vivo metabolite of CHCl 3, CBrCl 3, and CCl 4. After the administration of CHCl 3, CBrCl 3, and CCl 4, 2.89, 0.64, or 0.11 μmol of GSCOSG, respectively, was excreted in 6 hr. These results suggest that CHCl 3, CBrCl 3, and CCl 4 are metabolized in vitro and in vivo to phosgene (COCl 2), which reacts with GSH to produce GSCOSG. The reaction of GSH with COCl 2 may be responsible at least in part for the GSH-depleting properties of CHCL 3, CBrCl 3, and CCl 4, inasmuch as the relative amounts of formation of GSCOSG in vitro and in vivo paralleled their relative GSH-depleting activities.

AB - One hour after the intraperitoneal administration of CHCl 3, CBrCl 3, or CCl 4 to phenobarbital (PB)-treated rats, hepatic GSH levels decreased to 30, 59, and 88% of control levels, respectively; after 4 hr, the GSH levels had returned to 46, 65, 99%, respectively, of control levels. When incubated for 15 min in air with rat liver microsomes from PB-treated rats, a NADPH-generating system, and GSH (5 mM), all of the compounds were converted to diglutathionyl dithiocarbonate (GSCOSG). The rate of conversion of CHCl 3, CBrCl 3, and CCl 4 to GSCOSG was 180, 58, and 8 nmol per mg of protein per 15 min, respectively. The GSCOSG was also identified in bile by 13C-NMR spectroscopy and HPLC as an in vivo metabolite of CHCl 3, CBrCl 3, and CCl 4. After the administration of CHCl 3, CBrCl 3, and CCl 4, 2.89, 0.64, or 0.11 μmol of GSCOSG, respectively, was excreted in 6 hr. These results suggest that CHCl 3, CBrCl 3, and CCl 4 are metabolized in vitro and in vivo to phosgene (COCl 2), which reacts with GSH to produce GSCOSG. The reaction of GSH with COCl 2 may be responsible at least in part for the GSH-depleting properties of CHCL 3, CBrCl 3, and CCl 4, inasmuch as the relative amounts of formation of GSCOSG in vitro and in vivo paralleled their relative GSH-depleting activities.

UR - http://www.scopus.com/inward/record.url?scp=0019481016&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0019481016&partnerID=8YFLogxK

M3 - Article

C2 - 6114833

AN - SCOPUS:0019481016

VL - 9

SP - 334

EP - 339

JO - Drug Metabolism and Disposition

JF - Drug Metabolism and Disposition

SN - 0090-9556

IS - 4

ER -