Skip to main content
Log in

Toxicokinetic study of pyrrole adducts and its potential application for biological monitoring of 2,5-hexanedione subacute exposure

  • Original Article
  • Published:
International Archives of Occupational and Environmental Health Aims and scope Submit manuscript

Abstract

Purpose

The formation of pyrrole adducts might be responsible for peripheral nerve injury caused by n-hexane, but there is not an effective biomarker for monitoring occupational exposure of n-hexane. The current study was designed to investigate the changes of pyrrole adducts in serum and urine of rats exposed to 2,5-hexanedione (2,5-HD) and analyze the correlation between pyrrole adducts and 2,5-HD.

Methods

Two groups of male Wistar rats (n = 8) were administered a single dose of 200 and 400 mg/kg 2,5-HD (i.p.), and another two groups (n = 8) were given daily dose of 200 and 400 mg/kg 2,5-HD (i.p.) for 5 days. Pyrrole adducts and 2,5-HD in serum and urine were determined, at different time points after dosing, using Ehrlich’s reagent and gas chromatography, respectively.

Results

The levels of pyrrole adducts in serum accumulated in a time-dependant manner after repeated exposure to 2,5-HD, while pyrrole adducts in urine, and 2,5-HD in serum and urine were kept stable. The half-life times (t 1/2) of 2,5-HD and pyrrole adducts in serum were 2.27 ± 0.28 and 25.3 ± 3.34 h, respectively. Furthermore, the levels of pyrrole adducts in urine were significantly correlated with the levels of 2,5-HD in serum (r = 0.736, P < 0.001) and urine (r = 0.730, P < 0.001), and the levels of pyrrole adducts in serum were correlated with the cumulative dosage of 2,5-HD (r = 0.965, P < 0.001).

Conclusion

The results suggested that pyrrole adducts in serum and urine might be markers of chronic exposure to n-hexane or 2,5-HD.

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.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Alessio L, Berlin A, Dell’Orto A, Toffoletto F, Ghezzi I (1985) Reliability of urinary creatinine as a parameter used to adjust values of urinary biological indicators. Int Arch Occup Environ Health 55(2):99–106

    Article  CAS  Google Scholar 

  • Couri D, Abdel-Rahman MS, Hetland LB (1978) Biotransformation of n-hexane and methyl n-butyl ketone in guinea pigs and mice. Am Ind Hyg Assoc J 39(4):295–300. doi:10.1080/0002889778507761

    Article  CAS  Google Scholar 

  • DeCaprio AP, O’Neill EA (1985) Alterations in rat axonal cytoskeletal proteins induced by in vitro and in vivo 2,5-hexanedione exposure. Toxicol Appl Pharmacol 78(2):235–247

    Article  CAS  Google Scholar 

  • DeCaprio AP, Olajos EJ, Weber P (1982) Covalent binding of a neurotoxic n-hexane metabolite: conversion of primary amines to substituted pyrrole adducts by 2,5-hexanedione. Toxicol Appl Pharmacol 65(3):440–450

    Article  CAS  Google Scholar 

  • DeCaprio AP, Strominger NL, Weber P (1983) Neurotoxicity and protein binding of 2,5-hexanedione in the hen. Toxicol Appl Pharmacol 68(2):297–307

    Article  CAS  Google Scholar 

  • DeCaprio AP, Kinney EA, Fowke JH (1997) Regioselective binding of 2,5-hexanedione to high-molecular-weight rat neurofilament proteins in vitro. Toxicol Appl Pharmacol 145(1):211–217. doi:10.1006/taap 1997.8181

    Article  CAS  Google Scholar 

  • dos Santos CR, Meyer Passarelli MM, de Nascimento Souza E (2002) Evaluation of 2,5-hexanedione in urine of workers exposed to n-hexane in Brazilian shoe factories. J Chromatogr B Analyt Technol Biomed Life Sci 778(1–2):237–244

    Article  Google Scholar 

  • Fedtke N, Bolt HM (1986) Methodological investigations on the determination of n-hexane metabolites in urine. Int Arch Occup Environ Health 57(2):149–158

    Article  CAS  Google Scholar 

  • Fedtke N, Bolt HM (1987) The relevance of 4,5-dihydroxy-2-hexanone in the excretion kinetics of n-hexane metabolites in rat and man. Arch Toxicol 61(2):131–137

    Article  CAS  Google Scholar 

  • Genter St Clair MB, Amarnath V, Moody MA, Anthony DC, Anderson CW, Graham DG (1988) Pyrrole oxidation and protein cross-linking as necessary steps in the development of gamma-diketone neuropathy. Chem Res Toxicol 1(3):179–185

    Article  CAS  Google Scholar 

  • Graham DG, Anthony DC, Boekelheide K (1982) In vitro and in vivo studies of the molecular pathogenesis of n-Hexane neuropathy. Neurobehav Toxicol Teratol 4(6):629–634

    CAS  Google Scholar 

  • Greenberg GN, Levine RJ (1989) Urinary creatinine excretion is not stable: a new method for assessing urinary toxic substance concentrations. J Occup Med 31(10):832–838

    Article  CAS  Google Scholar 

  • Johnson DJ, Lack L, Ibrahim S, Abdel-Rahman SM, Abou-Donia MB (1995) Protein-bound pyrroles in rat hair following subchronic intraperitoneal injections of 2,5-hexanedione. J Toxicol Environ Health 45(3):313–324. doi:10.1080/15287399509531998

    Article  CAS  Google Scholar 

  • Kawai T, Mizunuma K, Yasugi T, Uchida Y, Ikeda M (1990) The method of choice for the determination of 2,5-hexanedione as an indicator of occupational exposure to n-hexane. Int Arch Occup Environ Health 62(5):403–408

    Article  CAS  Google Scholar 

  • Kessler W, Heilmaier H, Kreuzer P, Shen JH, Filser M, Filser JG (1990) Spectrophotometric determination of pyrrole-like substances in urine of rat and man: an assay for the evaluation of 2,5-hexanedione formed from n-hexane. Arch Toxicol 64(3):242–246

    Article  CAS  Google Scholar 

  • Manini P, Andreoli R, Mutti A, Bergamaschi E, Franchini I (1999) Determination of free and glucuronated hexane metabolites without prior hydrolysis by liquid- and gas-chromatography coupled with mass spectrometry. Toxicol Lett 108(2–3):225–231

    Article  CAS  Google Scholar 

  • Mattocks AR, White IN (1970) Estimation of metabolites of pyrrolizidine alkaloids in animal tissues. Anal Biochem 38(2):529–535

    Article  CAS  Google Scholar 

  • Mayan O, Teixeira JP, Pires AF (2001) Biological monitoring of n-hexane exposure in Portuguese shoe manufacturing workers. Appl Occup Environ Hyg 16(7):736–741. doi:10.1080/10473220116711

    Article  CAS  Google Scholar 

  • Mayan O, Teixeira JP, Alves S, Azevedo C (2002) Urinary 2,5 hexanedione as a biomarker of n-hexane exposure. Biomarkers 7(4):299–305. doi:10.1080/13547500210136796

    Article  CAS  Google Scholar 

  • Misumi J, Nagano M, Futatsuka M, Zhao W, Kudo M (1997) Different administration schedules of the same dose of 2,5-hexanedione influence the development of neuropathy and the toxicokinetics. Neurochem Res 22(1):27–32

    Article  CAS  Google Scholar 

  • Perbellini L, Brugnone F, Pastorello G, Grigolini L (1979) Urinary excretion of n-hexane metabolites in rats and humans. Int Arch Occup Environ Health 42(3–4):349–354

    Article  CAS  Google Scholar 

  • Perbellini L, Amantini MC, Brugnone F, Frontali N (1982) Urinary excretion of n-hexane metabolites. A comparative study in rat, rabbit and monkey. Arch Toxicol 50(3–4):203–215

    Article  CAS  Google Scholar 

  • Perbellini L, Mozzo P, Olivato D, Brugnone F (1990) “Dynamic” biological exposure indexes for n-hexane and 2,5-hexanedione, suggested by a physiologically based pharmacokinetic model. Am Ind Hyg Assoc J 51(7):356–362. doi:10.1080/15298669091369781

    Article  CAS  Google Scholar 

  • Perbellini L, Pezzoli G, Brugnone F, Canesi M (1993) Biochemical and physiological aspects of 2,5-hexanedione: endogenous or exogenous product? Int Arch Occup Environ Health 65(1):49–52

    Article  CAS  Google Scholar 

  • Schaumburg HH, Spencer PS (1976) Degeneration in central and peripheral nervous systems produced by pure n-hexane: an experimental study. Brain 99(2):183–192

    Article  CAS  Google Scholar 

  • Shaw G, Hou ZC (1990) Bundling and cross-linking of intermediate filaments of the nervous system. J Neurosci Res 25(4):561–568. doi:10.1002/jnr.490250414

    Article  CAS  Google Scholar 

  • Toutain PL, Bousquet-Melou A (2004) Plasma terminal half-life. J Vet Pharmacol Ther 27(6):427–439. doi:10.1111/j.1365-2885.2004.00600.x

    Article  CAS  Google Scholar 

  • van Engelen JG, Rebel-de Haan W, Opdam JJ, Mulder GJ (1997) Effect of coexposure to methyl ethyl ketone (MEK) on n-hexane toxicokinetics in human volunteers. Toxicol Appl Pharmacol 144(2):385–395. doi:10.1006/taap 1997.8149

    Article  Google Scholar 

  • Veulemans H, Van Vlem E, Janssens H, Masschelein R, Leplat A (1982) Experimental human exposure to n-Hexane. Study of the respiratory uptake and elimination, and of n-Hexane concentrations in peripheral venous blood. Int Arch Occup Environ Health 49(3–4):251–263

    Article  CAS  Google Scholar 

  • Yasui T, Zhao W, Misumi J, Aoki K, Shimaoka A, Kudo M (1995) Influence of different doses of methyl ethyl ketone on 2,5-hexanedione concentrations in the sciatic nerve, serum, and urine of rats. Sangyo Eiseigaku Zasshi 37(1):19–24

    Article  CAS  Google Scholar 

  • Zhu M, Spink DC, Yan B, Bank S, DeCaprio AP (1994) Formation and structure of cross-linking and monomeric pyrrole autoxidation products in 2,5-hexanedione-treated amino acids, peptides, and protein. Chem Res Toxicol 7(4):551–558

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by grants from Doctoral Fund of Ministry of Education of China (20120131110058) and National Natural Science Foundation of China (81373044).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ke-Qin Xie.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 73 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yin, HY., Guo, Y., Song, FY. et al. Toxicokinetic study of pyrrole adducts and its potential application for biological monitoring of 2,5-hexanedione subacute exposure. Int Arch Occup Environ Health 87, 655–662 (2014). https://doi.org/10.1007/s00420-013-0907-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00420-013-0907-4

Keywords

Navigation