Skip to main content
Log in

Evidence for hydroxyl free radical formation during paraquat but not for nifurtimox liver microsomal biotransformation. A dimethyl-sulfoxide scavenging study

  • Original Investigations
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

The effect of several experimental conditions on methane (CH4) production from dimethylsulfoxide (DMSO) in incubation mixtures containing liver microsomes and NADPH generating systems was studied. The process was heat sensitive in part but a significant fraction was non-enzymatic in nature. CH4 formation from DMSO was not significantly modified by 2-diethylaminoethyl-2,2-diphenylvalerate. HC1 (SKF 525 A) or EDTA 1 mM and significantly enhanced under an atmosphere of (CO 80%+O2 20%) rather than under air. A marked increase in CH4 production was observed when paraquat (PQ) was included in incubation mixtures but not when nifurtimox (Nfx) was added. Results support the hypothesis of hydroxyl free radical (·OH) formation during PQ biotransformation but cast doubts about its production for the case of Nfx. The low temperature gas chromatographic separation of d3-CH4 from CH4 described opens the future possibility for detecting trace formation of ·OH in vivo, without interference from fecal CH4 formation by administering d6-DMSO to animals and collecting exhaled gases produced, in chambers containing the entire animal.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Aguilar EG, Arranz CK de, Toranzo EGD de, Castro JA (1985) Benznidazole and Nifurtimox nitroreductase activity in liver microsomes from male rats pre-induced with phenobarbital or 3-methylcholanthrene. Res Commun Chem Pathol Pharmacol 50: 443–446

    Google Scholar 

  • Baldwin RC, Pasi A, MacGregor JT, Hine CM (1975) The rates of radical formation from dipyridilium herbicides, paraquat, diquat and morfamquat in homogenates of rat lung, kidney and liver. Toxicol Appl Pharmacol 32: 298–304

    Google Scholar 

  • Bancroft H (1960) Introduction a la bioestadística. EUDEBA, Buenos Aires, pp 205–211

    Google Scholar 

  • Bernacchi AS, Castro CR de, Toranzo EGD, Castro JA (1986) Effects of nifurtimox or benznidazole administration on rat testes: ultrastructural observations and biochemical studies. Exp Mol Pathol 45: 245–256

    Google Scholar 

  • Bus JS, Gibson JE (1984). Paraquat: model for oxidant initiated toxicity. Environ Health Perspect 55: 37–46

    Google Scholar 

  • Cadenas E, Brigelius R, Sies H (1983) Paraquat-induced chemiluminiscence of microsomal fractions. Biochem Pharmacol 32: 147–150

    Google Scholar 

  • Castro GD, Castro JA (1985) Studies on pentane evolution by rats treated with nirfurtimox or benznidazole. Toxicology 35: 319–326

    Google Scholar 

  • Castro JA, Gillette JR (1967) Species and sex differences in the kinetic constants for the N-demethylation of ethyl morphine by liver microsomes. Biochem Biophys Res Commun 28: 426–430

    Google Scholar 

  • Castro JA, Toranzo EGD de (1988) Toxic side effects of nifurtimox and benznidazole, two drugs used against American Trypanosomiasis (Chagas' Disease). Biomed Environ Sci (in press)

  • Cohen G, Cederbaum AI (1979) Chemical evidence for production of hydroxyl radicals during microsomal electron transfer. Science 204: 66–68

    Google Scholar 

  • Docampo R, Mason RP, Mottley C, Muniz RPA (1981a) Generation of free radicals induced by nifurtimox in mammalian tissues. J Biol Chem 256: 10930–10933

    Google Scholar 

  • Docampo R, Moreno SNJ (1985) Biochemical toxicolgy of antiparasitic compounds used in the chemotherapy and chemoprophylaxis of American Trypanosomiasis (Chagas' Disease). Rev Biochem Toxicol 7: 159–204

    Google Scholar 

  • Docampo R, Moreno SNJ, Stoppani AOM (1981b) Nitrofuran enhancement of microsomal electron transport, superoxide anion production and lipid peroxidation. Arch Biochem Biophys 207: 316–324

    Google Scholar 

  • Dubin M, Grinblat L, Fernández Villamil SH, Stoppani AOM (1987a) Inhibición de la lipoperoxidación en microsomas de hígado por Nifurtimox y Nitrofurantoína. Medicina 47: 342–350

    Google Scholar 

  • Dubin M, Grinblat L, Fernández Villamil SH, Stoppani AOM (1987b). Nitrofuran inhibition of microsomal lipid peroxidation. FEBS Lett 220: 197–200

    Google Scholar 

  • Dubin M, Moreno SNJ, Martino EE, Docampo R, Stoppani AOM (1983) Increased biliary secretion and loss of hepatic glutathione in rat liver after nifurtimox treatment. Biochem Pharmacol 32: 483–487

    Google Scholar 

  • Fairshter RD, Vaziri ND, Dearden LC, Malott K, Caseño M (1984) Effect of dimethylthiourea on paraquat toxicity in rats. Toxicol Appl Pharmacol 74: 150–154

    Google Scholar 

  • Klein SM, Cohen G, Cederbaun AI (1981) Production of formaldehyde during metabolism of dimethylsulfoxide by hydroxyl radical generating systems. Biochemistry 20: 6006–6012

    Google Scholar 

  • Repine JE, Eaton JW, Anders MW, Hoidal JR, Fox RB (1979) Generation of hydroxyl radical by enzymes, chemicals, and human phagocytes in vitro. J Clin Invest 64: 1642–1651

    Google Scholar 

  • Smith LL (1985) Paraquat toxicity. Philos Trans R Soc Lond B 311: 647–657

    Google Scholar 

  • Smith LL (1987) Mechanism of paraquat toxicity and its relevance to treatment. Hum Toxicol 6 (Suppl): 31–36

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Additional information

This work was supported by Grant AM 13 195-18 from the National Institutes of Health (USA)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Castro, G.D., Lopez, A. & Castro, J.A. Evidence for hydroxyl free radical formation during paraquat but not for nifurtimox liver microsomal biotransformation. A dimethyl-sulfoxide scavenging study. Arch Toxicol 62, 355–358 (1988). https://doi.org/10.1007/BF00293623

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00293623

Key words

Navigation