Skip to main content
Top
Published in: International Archives of Occupational and Environmental Health 6/2014

01-08-2014 | Original Article

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

Authors: Hong-Yin Yin, Ying Guo, Fu-Yong Song, Tao Zeng, Ke-Qin Xie

Published in: International Archives of Occupational and Environmental Health | Issue 6/2014

Login to get access

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.
Appendix
Available only for authorised users
Literature
go back to reference 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):99–106CrossRef 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):99–106CrossRef
go back to reference 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):235–247CrossRef 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):235–247CrossRef
go back to reference 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):440–450CrossRef 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):440–450CrossRef
go back to reference DeCaprio AP, Strominger NL, Weber P (1983) Neurotoxicity and protein binding of 2,5-hexanedione in the hen. Toxicol Appl Pharmacol 68(2):297–307CrossRef DeCaprio AP, Strominger NL, Weber P (1983) Neurotoxicity and protein binding of 2,5-hexanedione in the hen. Toxicol Appl Pharmacol 68(2):297–307CrossRef
go back to reference 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 1997.8181CrossRef 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 1997.8181CrossRef
go back to reference 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):237–244CrossRef 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):237–244CrossRef
go back to reference Fedtke N, Bolt HM (1986) Methodological investigations on the determination of n-hexane metabolites in urine. Int Arch Occup Environ Health 57(2):149–158CrossRef Fedtke N, Bolt HM (1986) Methodological investigations on the determination of n-hexane metabolites in urine. Int Arch Occup Environ Health 57(2):149–158CrossRef
go back to reference 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):131–137CrossRef 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):131–137CrossRef
go back to reference 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):179–185CrossRef 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):179–185CrossRef
go back to reference 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 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
go back to reference 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):832–838CrossRef 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):832–838CrossRef
go back to reference 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 CrossRef 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/​1528739950953199​8 CrossRef
go back to reference 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):403–408CrossRef 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):403–408CrossRef
go back to reference 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):242–246CrossRef 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):242–246CrossRef
go back to reference 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):225–231CrossRef 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):225–231CrossRef
go back to reference Mattocks AR, White IN (1970) Estimation of metabolites of pyrrolizidine alkaloids in animal tissues. Anal Biochem 38(2):529–535CrossRef Mattocks AR, White IN (1970) Estimation of metabolites of pyrrolizidine alkaloids in animal tissues. Anal Biochem 38(2):529–535CrossRef
go back to reference 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):27–32CrossRef 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):27–32CrossRef
go back to reference 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):349–354CrossRef 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):349–354CrossRef
go back to reference 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):203–215CrossRef 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):203–215CrossRef
go back to reference 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 CrossRef 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/​1529866909136978​1 CrossRef
go back to reference 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):49–52CrossRef 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):49–52CrossRef
go back to reference Schaumburg HH, Spencer PS (1976) Degeneration in central and peripheral nervous systems produced by pure n-hexane: an experimental study. Brain 99(2):183–192CrossRef Schaumburg HH, Spencer PS (1976) Degeneration in central and peripheral nervous systems produced by pure n-hexane: an experimental study. Brain 99(2):183–192CrossRef
go back to reference 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 1997.8149CrossRef 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 1997.8149CrossRef
go back to reference 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):251–263CrossRef 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):251–263CrossRef
go back to reference 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):19–24CrossRef 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):19–24CrossRef
go back to reference 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):551–558CrossRef 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):551–558CrossRef
Metadata
Title
Toxicokinetic study of pyrrole adducts and its potential application for biological monitoring of 2,5-hexanedione subacute exposure
Authors
Hong-Yin Yin
Ying Guo
Fu-Yong Song
Tao Zeng
Ke-Qin Xie
Publication date
01-08-2014
Publisher
Springer Berlin Heidelberg
Published in
International Archives of Occupational and Environmental Health / Issue 6/2014
Print ISSN: 0340-0131
Electronic ISSN: 1432-1246
DOI
https://doi.org/10.1007/s00420-013-0907-4

Other articles of this Issue 6/2014

International Archives of Occupational and Environmental Health 6/2014 Go to the issue