Skip to main content
SpringerLink
Log in

1,2-Dichloropropane (DCP) toxicity is correlated with DCP-induced glutathione (GSH) depletion and is modulated by factors affecting intracellular GSH

  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

Acute 1,2-dichloropropane (DCP) poisoning in humans is relatively frequent in Italy, where DCP is widely diffused as a constituent of commercial solvents and dry cleaners. In this study we have investigated the effects of DCP on intracellular glutathione (GSH) content in main target tissues of male Wistar rats, i.e. liver, kidney and blood, in order to establish if a correlation between DCP-induced GSH depletion and tissue damage exists. Administration of DCP (2 ml/kg body weight orally) caused a dramatic loss of tissue GSH occurring 24 h after DCP intoxication, followed by a slow restoration approaching physiological levels after 96 h. GSH depletion was associated with a marked increase in serum GOT, GPT, 5′-nucleotidase, gamma-glutamyl transpeptidase, alkaline phosphatase, urea and creatinine, and a significant degree of hemolysis. When animals were pretreated with a GSH depleting agent, buthionine-sulfoximine (BSO) (0.5 g/kg body weight) i. p. 4 h before DCP intoxation, an increase of overall mortality was found, significantly different from the group of animals treated with DCP alone. On the contrary, the administration of a GSH precursor, N-acetylcysteine (NAC) i. p. (250 mg/kg body weight) 2 and 16 h after DCCP intoxication prevented the dramatic loss of cellular GSH and reduced the extent of injury in target tissues, as demonstrated by laboratory indices. Furthermore, statistical analysis of the data revealed a correlation between: (1) depletion of liver GSH and increase in serum GOT, GPT, 5′-nucleotidase, (2) depletion of kidney GSH and increase in serum urea and creatinine and (3) depletion of blood GSH and the occurence of hemolysis. Our findings demonstrate that GSH plays a critical role in modulating the toxicity of DCP. They also highlight the protective role of NAC and suggest that this glutathione precursor could rationally be employed in DCP poisoning in humans.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

BSO:

DL-buthionine-[S,R]-sulfoximine

DCP:

1,2-Dichloropropane

gamma-GT:

gamma-glutamyl transpeptide

GOT:

glutamic oxaloacetic transaminase

GPT:

glutamic pyruvic transaminase

GSH:

glutathione, reduced form

GSSG:

glutathione disulfide

HPLC:

high performance liquid chromatography

PCA:

perchloric acid

References

  • Andrews LS, Snyder R (1986) Toxic effects of solvents and vapors. In: Klassen CD, Amdur MO, Doull J (eds) Casarett and Doull's Toxicology, third edition. Macmillan Publishing company, New York. pp 636–668

    Google Scholar 

  • Arkesteijn CLM (1976) A kinetic method for serum 5′-nucleotidase using stabilized glutamate dehydrogenase. J Clin Chem Clin Biochem 14: 155

    Google Scholar 

  • Bellomo G, Orrenius S (1985) Altered thiol and calcium homeostasis in oxidative hepatocellular injury. Hepatology 5: 876–882

    Google Scholar 

  • Brezis M, Rosen S, Silva P, Epstein FH (1983) Selective glutathione depletion on function and structure of the isolated perfused rat kidney. Kidney Int 24: 178–184

    Google Scholar 

  • Brucato A, Ruggeroni ML, Locatelli C, Fincato F, Maccarini D, Ghezzi-Laurenzi R (1986) Trattamento intensivo delle epatiti acute tossiche da 1,2-dicloropropano. Atti del XL Congresso SIAARTI, Pavia, p 194

  • Casini AF, Maellaro E, Pompella A, Ferrali M, Comporti M (1987) Lipid peroxidation, protein thiols and calcium homeostasis in bromobenzene-induced liver damage. Biochem Pharmacol 36: 3689–3695

    Google Scholar 

  • Chiappino G, Secchi GC (1968) Description of a case of acute poisoning from accidental ingestion of 1,2-dichloropropane sold as tirlene. Med Lav 5: 334–341

    Google Scholar 

  • Dawson JR, Norbeck K, Anundi I, Moldeus P (1984) The effectiveness of N-acetylcysteine in isolated hepatocytes, against the toxicity of paracetamol, acrolein, and paraquat. Arch Toxicol 55: 11–15

    Google Scholar 

  • Di Monte, Bellomo G, Thor H, Nicotera P, Orrenius S (1984) Menadione-induced cytotoxicity is associated with protein thiol oxidation and alteration in intracellular Ca2+ homeostasis. Arch Biochem Biophys 235: 343–350

    Google Scholar 

  • Freeman RW, MacDonald JS, Olson RD, Boerth RC, Oates JA, Harbison RD (1980) Effect of sulphydryl-containing compounds on the antitumor effects of adriamycin. Toxicol Appl Pharmacol 54: 168–175

    Google Scholar 

  • Heppel LA, Neal PA, Highman B, Porterfield VT (1946) Toxicology of 1,2-dichloropropane. I. Studies on effects of daily inhalations. J Ind Hyg Toxicol 28: 1–8

    Google Scholar 

  • Hutson DH, Moss JA, Pickering A (1971) The excretion and retention of components of the soil fumigant D-D and their metabolites in the rat. Food Cosmet Toxicol 9: 677–680

    Google Scholar 

  • Imberti R, Calabrese SR, Emilio G, Marchi L, Giuffrida L (1987) Intossicazione acuta da solventi: idrocarburi alifatici clorurati. Min Anest 53: 399–403

    Google Scholar 

  • Johnson GJ, Allen DW, Cadman S, Fairbanks VF, White JG, Lampkin BC, Kaplan ME (1979) Red-cell membrane polypeptide aggregates in glucose-6-phosphate dehydrogenase mutants with chronic hemolytic disease. N Engl J med 301: 522–527

    Google Scholar 

  • Jones AR, Gibson J (1980) 1,2-Dichloropropane: metabolism and fate in the rat. Xenobiotica 10: 835–846

    Google Scholar 

  • Ketterer B, Coles B, Meyer DJ (1983) The role of glutathione in detoxication. Environ Health Perspect 49: 59–69

    Google Scholar 

  • Kosower NS, Kosower ED (1983) Glutathione and cell membrane thiol status. Larsson et al. (eds), In: Functions of glutathione: biochemical, physiological, toxicological, and clinical aspects, p 307–315

  • Lauterburg BH, Smith CV, Hughes H, Mitchell JR (1982): Determinants of hepatic glutathione turnover: toxicological significance. TIPS 245–248

  • Lauterburg BH, Corcoran GB, Mitchell JR (1983) Mechanism of action of N-acetylcysteine in the protection against the hepatotoxicity of acetaminophen in rats in vivo. J Clin Invest 71: 980–991

    Google Scholar 

  • Massey TE, Racz WJ (1981) Effects of N-acetylcysteine on metabolism, covalent binding, and toxicity of acetaminophen in isolated mouse hepatocytes. Toxicol Appl Pharmacol 60: 220–228

    Google Scholar 

  • Meister A (1983) Metabolism and transport of glutathione and other gamma-glutamyl compounds. In: Larsson A, Orrenius S, Holmgren A, Mannervik B (eds) Functions of glutathione: biochemical, physiological, toxicological and clinical aspects. Raven Press, New York, pp 1–22

    Google Scholar 

  • Mitchell JR, Jollow DJ, Potter WZ, Gilette JR, Brodie BB (1973) Acetaminophen induced hepatic damage. IV. Protective role of glutathione. J Pharmacol Exp Ther 1877: 211–217

    Google Scholar 

  • Orrenius S, Thor H, Bellomo G, Moldeus P (1984) Glutathione and tissue toxicity. Proceedings of the IUPHAR 9th International congress of Pharmacology, vol. 2, pp 57–66

    Google Scholar 

  • Orrenius S, Thor H, McConkey D, Nicotera P, Bellomo G (1989) Mechanism of cell toxicity: the thiol/calcium hypothesis. In: Proceedings of the VIIth International Symposium on Microsomes and Drug Oxidation. Taylor and Francis, London 329–337

    Google Scholar 

  • Ponticelli C, Imbasciati E, Redaelli B, Salvadeo A (1968) Insufficienza epato-renale acuta da trielina. Lav Umano 20: 205–212

    Google Scholar 

  • Pozzi C, Marai P, Ponti R, Dell'Oro C, Sala C, Zedda S, Locatelli F (1985) Toxicity in man due to stain removers containing 1,2-Dichloropropane. Br J Ind Med 42: 770–772

    Google Scholar 

  • Prescott LF, Park J, Ballantyne A, Adriaenssens P, Proudfoot AT (1977) Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine. Lancet II: 432–434

    Google Scholar 

  • Recommendations of the German Society for Clinical Chemistry (1970) Standardisation of methods for the estimation of enzyme activities in biological fluids. J Clin Chem Clin Biochem 8: 659–660

    Google Scholar 

  • Recommendations of the German Society for Clinical Chemistry (1971) Standardisation of methods for the estimation of enzyme activities in biological fluids. J Clin Chem Clin Biochem 9: 464–465

    Google Scholar 

  • Recommendations of the German Society for Clinical Chemistry (1972) Standardisation of methods for the estimation of enzyme activities in biology fluids. J Clin Chem Clin Biochem 10: 281–291

    Google Scholar 

  • Reed DJ, Babson JR, Beatty PW, Brodie AE, Ellis WW, Potter DW (1980) High-performance liquid chromatography analysis of nanomole levels of glutathione disulfide, and related thiols and disulfides. Anal Biochem 106: 55–62

    Google Scholar 

  • Reed DJ, Brodie AE, Meredith MJ (1983) Cellular heterogeneity in the status and functions of cysteine and glutathione. In: Larsson A, Orrenius S, Holmgren A, Mannervik B (eds) Functions of glutathione: biochemical, physiological, toxicological and clinical aspects. Raven Press, New York, pp 39–48

    Google Scholar 

  • Ruprah M, Mant TGK, Flanagan RJ (1985) Acute carbon tetrachloride poisoning in 19 patients: implications for diagnosis and treatment. Lancet I: 1027–1029

    Google Scholar 

  • Secchi GC, Chiappino G, Lotto A, Zurlo N (1968) Actual chemical compositon of the “commercial trichloroethylenes” and their liver toxcity. Clinical and enzymological studies. Med Lav 59: 486–497

    Google Scholar 

  • Singhal RH, Anderson ME, Meister A (1987) Glutathione, a first line of defence against cadmium toxicity. FASEB J 1: 220–223

    Google Scholar 

  • Stevens JL, Ayoubi N, Robbins JD (1988) The role of mitochondrial matrix enzymes in the metabolism and toxicity of cysteine conjugates. J Biol Chem 263: 3395–3401

    Google Scholar 

  • Szasz G (1974) Methods of enzymatic analysis. Second English Edition, Verlag Chemie, Academic Press, p 715

  • Tomasini M (1976) Cardiac arrythmias due to intoxication by trichloroethylene (“tri”). Med Lav 67: 163–169

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Servizio di Anestesia e Rianimazione II, IRCCS Policlinico S. Matteo, Italy

    R. Imberti & A. Mapelli

  2. Servizio di Analisi Chimico-Cliniche, IRCCS Policlinico S. Matteo, Italy

    P. Colombo

  3. Istituto di Farmacologia II, University of Pavia, 27100, Pavia, Italy

    P. Richelmi & F. Bertè

  4. Istituto di Clinica Medica I, University of Pavia, 27100, Pavia, Italy

    G. Bellomo

Authors
  1. R. Imberti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Mapelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. Colombo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. Richelmi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F. Bertè
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G. Bellomo
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Imberti, R., Mapelli, A., Colombo, P. et al. 1,2-Dichloropropane (DCP) toxicity is correlated with DCP-induced glutathione (GSH) depletion and is modulated by factors affecting intracellular GSH. Arch Toxicol 64, 459–465 (1990). https://doi.org/10.1007/BF01977627

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01977627

Key words

Search

Navigation