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International Archives of Occupational and Environmental Health

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01.02.2008 | Original Article

Influence of polymorphic metabolic enzymes on biotransformation and effects of diphenylmethane diisocyanate

verfasst von: Margareta Littorin, Saimei Hou, Karin Broberg, Jonas Björk, Susanne Fält, Galbani Abdoulaye, Malgorzata Kalemba, Charlotta Ryk, Staffan Skerfving

Erschienen in: International Archives of Occupational and Environmental Health | Ausgabe 4/2008

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Abstract

Objectives

To identify effect modification produced by genetic traits found in metabolic enzymes, to investigate how these affect the levels of different biomarkers of sprayed and thermo-degraded polyurethane (PUR) based on 4,4′-diphenylmethane diisocyanate (MDI) and to determine how associated respiratory disorders are affected.

Methods

Two partly overlapping groups of 141 and 158 factory employees exposed to sprayed or heated MDI-PUR glue were examined in years 0 and 2, respectively, for occurrence of polymorphisms in five genes (N-acetyltransferase NAT2 and the glutathione S-transferases GSTM1, GSTM3, GSTP1 [codon 105 and 114] and GSTT1) on the basis of the polymerase chain reaction, exposure biomarkers in plasma and urine (P- and U-MDX), by means of gas chromatography-mass spectrometry, specific serum IgG antibodies against MDI (S-IgG-MDI) by means of ELISA, total S-IgE, symptoms in the eyes, nose and lower airways as assessed by questionnaire and interview, and lung function as measured by spirometry.

Results

Both the GSTP1 ¹⁰⁵ isoleucine/isoleucine and GSTP1 ¹¹⁴ alanine/alanine genotypes showed higher levels of U-MDX than the other genotypes and the GSTP1 ¹¹⁴ genotype modified the P-MDX/U-MDX relationship. GSTP1 ¹⁰⁵ isoleucine/isoleucine was found to be associated with lower levels of S-IgG-MDI and fewer eye symptoms, but with an increased risk of symptoms in the airways, as well as with atopy. Presence of the GSTT1 gene resulted in somewhat lower lung function levels than did the null genotype. A slow NAT2 acetylating capacity was associated with lower P- and U-MDX and S-IgG-MDI levels, and better lung function, but a higher risk of eye and airway symptoms. Analysing the effects of combinations of the different genes provided no further information.

Conclusions

Although our study has clear limitations, it reveals various effect modifications produced by the GST and NAT2 genotypes. Gene-environment interactions are highly complex. Further research is needed to obtain a more comprehensive understanding of them.

American Thoracic Society (1987) Standardisation of spirometry: 1987 update. Am Rev Respir Dis 136:1285–1298

Anttila S, Hirvonen A, Vainio H, Husgafvel-Pursiainen K, Hayes JD, Ketterer B (1993) Immunohistochemical localization of glutathione S-transferases in human lung. Cancer Res 53:5643–5648PubMed

Barnes PJ (1990) Reactive oxygen species and airway inflammation. Free Radic Biol Med 9:235–243PubMedCrossRef

Baur X, Marek W, Ammon J, Czuppon AB, Marczynski B, Raulf-Heimsoth M, Roemmelt H, Fruhmann G (1994) Respiratory and other hazards of isocyanates. Int Arch Occup Environ Health 66:141–152PubMedCrossRef

Beghe B, Padoan M, Moss CT, Barton SJ, Holloway JW, Holgate ST, Howell WM, Mapp CE (2004) Lack of association of HLA class I genes and TNF alpha-308 polymorphism in toluene diisocyanate-induced asthma. Allergy 59:61–64PubMedCrossRef

Berglund E, Birath G, Bjure J, Grimby G, Kjellmer I, Sandqvist L, Söderholm B (1963) Spirometric studies in normal subjects. I. Forced expirograms in subjects between 7 and 70 years of age. Acta Med Scand 173:185–191PubMedCrossRef

Berode M, Jost M, Ruegger M, Savolainen H (2005) Host factors in occupational diisocyanate asthma: a Swiss longitudinal study. Int Arch Occup Environ Health 78:158–163PubMedCrossRef

Bolognesi C, Baur X, Marczynski B, Norppa H, Sepai O, Sabbioni G (2001) Carcinogenic risk of toluene diisocyanate and 4,4′-methylenediphenyl diisocyanate: epidemiological and experimental evidence. Crit Rev Toxicol 31:737–772PubMedCrossRef

Brown WE, Wold F (1971) Alkyl isocyanates as active site-specific inhibitors of chymotrypsin and elastase. Science 174:608–610PubMedCrossRef

Cascorbi I, Brockmöller J, Mrozikiewicz PM, Müller A, Roots I (1999) Arylamine N-acetyltransferase activity in man. Drug Met Rev 31:489–502CrossRef

Culp SJ, Roberts DW, Talaska G, Lang NP, Fu PP, Lay JO Jr, Teitel CH, Snawder JE, Von Tungeln LS, Kadlubar FF (1997) Immunochemical, 32P-postlabeling, and GC/MS detection of 4-aminobiphenyl-DNA adducts in human peripheral lung in relation to metabolic activation pathways involving pulmonary N-oxidation, conjugation, and peroxidation. Mutat Res 378:97–112PubMed

Dalene M, Jakobsson K, Rannug A, Skarping G, Hagmar L (1996) MDA in plasma as a biomarker of exposure to pyrolysed MDI-based polyurethane: correlations with estimated cumulative dose and genotype for N-acetylation. Int Arch Occup Environ Health 68:165–169PubMed

Dalene M, Skarping G, Lind P (1997) Workers exposed to thermal degradation products of TDI and MDI based polyurethane: biomonitoring of 2,4-TDA, 2,6-TDA, and 4,4′-MDA in hydrolysed urine and plasma. Am Ind Hyg Assoc J 58:587–591PubMed

Fryer AA, Bianco A, Hepple M, Jones PW, Strange RC, Spiteri MA (2000) Polymorphism at the glutathione s-transferase GSTP1 locus. A new marker for bronchial hyperresponsiveness and asthma. Am J Respir Crit Care Med 161:1437–1442PubMed

Garte S (2001) Metabolic susceptibility genes as cancer risk factors: time for a reassessment? Cancer Epidemiol Biomarkers Prev 10:1233–1237PubMed

Garte S, Gaspari L, Alexandrie AK, Ambrosone C, Autrup H, Autrup JL, Baranova H, Bathum L, Benthamou S, Boffetta P, Bouchardy C, Breskvar K, Brockmoller J, Cascorbi I, Clapper ML, Coutelle C, Daly A, Dell’Omo M, Dolzan V, Dresler CM, Fryer A, Haugen A, Hein DW, Hildesheim A, Hirvonen A, Hsieh LL, Ingelman-Sundberg M, Kalina I, Kang D, Kihara M, Kiyohara C, Kremers P, Lazarus P, Le Marchand L, Lechner MC, van Lieshout EM, London S, Manni JJ, Maugard CM, Morita S, Nazar-Stewart V, Noda K, Oda Y, Parl FF, Pastorelli R, Persson I, Peters WH, Rannug A, Rebbeck T, Risch A, Roelandt L, Romkes M, Ryberg D, Salagovic J, Schoket B, Seidegard J, Shields PG, Sim E, Sinnet D, Strange RC, Stucker I, Sugimura H, To-Figueras J, Vineis P, Yu MC, Taioli E (2001) Metabolic gene polymorphism frequencies in control populations. Cancer Epidemiol Biomarkers Prev 2001 10:1239–1248

Gauderman WJ (2002) Sample size requirements for association studies of gene-gene interaction. Am J Epidemiol 155:478–484PubMedCrossRef

Gilliland FD, Gauderman WJ, Vora H, Rappaport E, Dubeau L (2002) Effects of glutathione-S-transferase M1, T1, and P1 on childhood lung function growth. Am J Respir Crit Care Med 166:710–716PubMedCrossRef

Gledhill A, Wake A, Hext P, Leibold E, Shiotsuka R (2005) Absorption, distribution, metabolism and excretion of an inhalation dose of [14C] 4,4′-methylenediphenyl diisocyanate in the male rat. Xenobiotica 35:273–292PubMedCrossRef

Grant DM, Blum M, Meyer UA (1992) Polymorphisms of N-acetyltransferase genes. Xenobiotica 22:1073–1081PubMed

Hayes JD, Strange RC (1995) Potential contribution of the glutathione S-transferase supergene family to resistance to oxidative stress. Free Radic Res 22:193–207PubMedCrossRef

He JQ, Connett JE, Anthonisen NR, Pare PD, Sandford AJ (2004) Glutathione S-transferase variants and their interaction with smoking on lung function. Am J Respir Crit Care Med 170:388–394PubMedCrossRef

Hein DW, Doll MA, Fretland AJ, Leff MA, Webb SJ, Xiao GH, Devanaboyina US, Nangju NA, Feng Y (2000) Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms. Cancer Epidemiol Biomarkers Prev 9:29–41PubMed

Hou S-M, Lambert B, Hemminki K (1995) Relationship between hprt mutant frequency, aromatic DNA adducts and genotypes for GSM1 and NAT2 in bus maintenance workers. Carcinogenesis 16:1913–1917PubMedCrossRef

Jakobsson K, Rannug A, Alexandrie A-K, Rylander L, Hagmar L (1997) Airway symptoms and lung function in pipe-layers exposed to MDI-based polyurethane pyrolysis products and welding fumes do not relate to host polymorphism for CYP1A1, GSTM1 and NAT2. Biomarkers 2:57–62CrossRef

Johannesson G, SennbroCJ, Willix P, Lindh CH, Jonsson BA (2004a) Identification and characterisation of adducts between serum albumin and 4,4′-methylenediphenyl diisocyanate (MDI) in human plasma. Arch Toxicol 78:378–383PubMedCrossRef

Johannesson G, Lindh C, Nielsen J, Bjork B, Rosqvist S, Jonsson BA (2004b) In vivo conjugation of nasal lavage proteins by hexahydrophthalic anhydride. Toxicol Appl Pharmacol 194:69–78PubMedCrossRef

Kadlubar FF (1994) Biochemical individuality and its implications for drug and carcinogen metabolism: recent insights from acetyltransferase and cytochrome P4501A2 phenotyping and genotyping in humans. Drug Metab Rev 26:37–46PubMedCrossRef

Kautiainen A, Wachtmeister CA, Ehrenberg L (1998) Characterization of hemoglobin adducts from a 4,4′-methylenedianiline metabolite evidently produced by peroxidative oxidation in vivo. Chem Res Toxicol 11:614–621PubMedCrossRef

Kelly FJ (2003) Oxidative stress: its role in air pollution and adverse health effects. Occup Environ Med 60:612–616PubMedCrossRef

Kim SH, Oh HB, Lee KW, Shin ES, Kim CW, Hong CS, Nahm DH, Park HS (2006) HLA DRB1*15-DPB1*05 haplotype: a susceptible gene marker for isocyanate-induced occupational asthma? Allergy 61:891–894PubMedCrossRef

Kleeberger SR, Peden D (2005) Gene-environment interactions in asthma and other respiratory diseases. Annu Rev Med 56:383–400PubMedCrossRef

Lange RW, Day BW, Lemus R, Tyurin VA, Kagan VE, Karol MH (1999) Intracellular S-glutathionyl adducts in murine lung and human bronchoepithelial cells after exposure to diisocyanatotoluene. Chem Res Toxicol 12:931–936PubMedCrossRef

Lantz RC, Lemus R, Lange RW, Karol MH (2001) Rapid reduction of intracellular glutathione in human bronchial epithelial cells exposed to occupational levels of toluene diisocyanate. Toxicol Sci 60:348–355PubMedCrossRef

Lind P, Dalene M, Tinnerberg H, Skarping G (1997) Biomarkers in hydrolysed urine, plasma and erythrocytes among workers exposed to thermal degradation products from toluene diisocyanate foam. Analyst 122:51–56PubMedCrossRef

Littorin M, Rylander L, Skarping G, Dalene M, Welinder H, Strömberg U, Skerfving S (2000) Exposure biomarkers and risk at gluing and heating of polyurethane – a cross-sectional study of respiratory symptoms. Occup Environ Med 57:396–405PubMedCrossRef

Littorin M, Welinder H, Skarping G, Dalene M, Skerfving S (2002) Exposure and nasal inflammation in workers heating polyurethane. Int Arch Occup Environ Health 75:468–474PubMedCrossRef

Liu Q, Wisnewski AV (2003) Recent developments in diisocyanate asthma. Ann Allergy Asthma Immunol 90(Suppl):35–41PubMedCrossRef

Mapp CE, Beghe B, Balboni A, Zamorani G, Padoan M, Jovine L , Baricordi OR, Fabbri LM (2000) Association between HLA genes and susceptibility to toluene diisocyanate-induced asthma. Clin Exp Allergy 16:570–572

Mapp CE, Fryer AA, De Marzo N, Pozzato V, Padoan M, Boschetto P, Strange RC, Hemmingsen A, Spiteri MA (2002) Glutathione S-transferase GSTP1 is a susceptibility gene for occupational asthma induced by isocyanates. J Allergy Clin Immunol 109:867–872PubMedCrossRef

Mapp CE, Boschetto P, Miotto D, De Rosa E (2005) Asthma induced by isocyanates: a model of IgE-independent asthma. Acta Biomed Ateneo Parmense 76(Suppl 2):15–9

Park HS, Lee SK, Kim HY, Nahm DH, Kim SS (2002) Specific immunoglobulin E and immunoglobulin G antibodies to toluene diisocyanate-human serum albumin conjugate: useful markers for predicting long-term prognosis in toluene diisocyanate-induced asthma. Clin Exp Allergy 32:551–555PubMedCrossRef

Pelkonen O, Raunio H, Rautio A, Lang M. Chapter 8 (1999) Xenobiotic-metabolizing enzymes and cancer risk: correspondence between genotype and phenotype. In: Vineis P, Malats N, Lang M, d’Erricio A, Caporaso N, Cuzick J, Boffetta P (eds) Metabolic polymorphisms and susceptibility to cancer. Lyon: International Agency for Research on Cancer (IARC); p 77–88. IARC scientific publications, no 148

Pemble S, Schroeder KR, Spencer SR, Meyer DJ, Hallier E, Bolt HM, Ketterer B, Taylor JB (1994) Human glutathione S-transferase theta (GSTT1): cDNA cloning and the characterization of a genetic polymorphism. Biochem J 300:271–276PubMed

Piirilä P, Wikman H, Luukkonen R, Kääriä K, Rosenberg C, Nordman H, Norppa H, Vainio H, Hirvonen A (2001) Glutathione S-transferase genotypes and allergic responses to diisocyanate exposure. Pharmacogenetics 437–445

Raulf-Heimsoth M, Baur X (1998) Pathomechanisms and pathophysiology of isocyanate-induced diseases—summary of present knowledge. Am J Ind Med 34:137–143PubMedCrossRef

Rihs HP, Barbalho-Krölls T, Huber H, Baur X (1997) No evidence for the influence of HLA Class II in alleles in isocyanate-induced asthma. Am J Ind Med 32:522–527PubMedCrossRef

Savolainen H (1999) New mechanistic model for organic diisocyanate-induced respiratory disease. Schweiz Med Wochenschr 129:465–467PubMed

Schutze D, Sepai O, Lewalter J, Miksche L, Henschler D, Sabbioni G (1995) Biomonitoring of workers exposed to 4,4′-methylenedianiline or 4,4′-methylenediphenyl diisocyanate. Carcinogenesis 16:573–582PubMedCrossRef

Schwartzbaum JA, Ahlbom A, Lonn S, Warholm M, Rannug A, Auvinen A, Christensen HC, Henriksson R, Johansen C, Lindholm C, Malmer B, Salminen T, Schoemaker MJ, Swerdlow AJ, Feychting M (2007) An international case-control study of glutathione transferase, functionally related polymorphisms and risk of primary adult brain tumors. Cancer Epidemiol Biomarkers Prev 16(3):559–565PubMedCrossRef

Sepai O, Henschler D, Sabbioni G (1995) Albumin adducts, hemoglobin adducts and urinary metabolites in workers exposed to 4,4′-methylene diisocyanate. Carcinogenesis 16:2583–2587PubMedCrossRef

Sipes IG, Gandolfi AJ (1991) Biotransformation of toxicants. In: Amdur MO, Doull J, Klaassen CD (eds) Casarett and Doull’s Toxicology. Pergamon Press, New York, pp 88–126

Skarping G, Dalene M, Littorin M (1995) 4,4′-methylenedianiline in hydrolysed serum and urine from a worker exposed to thermal degradation products of methylene diphenyl diisocyanate elastomers. Int Arch Occup Environ Health 67:73–77PubMedCrossRef

Skarping G, Dalene M, Svensson B-G, Littorin M, Åkesson B, Welinder H, Skerfving S (1996) Biomarkers of exposure, antibodies, and respiratory symptoms in workers heating polyurethane glue. Occup Environ Med 53:180–187PubMedCrossRef

Tamer L, Calikoglu M, Ates NA, Yildirim H, Ercan B, Saritas E, Unlu A, Atik U (2004) Glutathione-S-transferase gene polymorphisms (GSTT1, GSTM1, GSTP1) as increased risk factors for asthma. Respirology 9:493–498PubMedCrossRef

Vineis P, Malats N, Lang M, d’Erricio A, Caporaso N, Cuzick J, Boffetta P (eds) (1999) Metabolic polymorphisms and susceptibility to cancer.Lyon: International Agency for Research on Cancer (IARC). IARC scientific publications no 148

Wikman H, Piirilä P, Rosenberg C, Luukkonen R, Kääriä K, Nordman H, Norppa H, Vainio H, Hirvonen A (2002) N-acetyltransferase genotypes as modifiers of diisocyanate exposure-associated asthma risk. Pharmacogenetics 12:227–233PubMedCrossRef

Windmill KF, Gaedigk A, Hall PM, Samaratunga H, Grant DM, McManus ME (2005) Localization of N-acetyltransferases NAT1 and NAT2 in human tissues. Toxicol Sci 54:19–29CrossRef

Wisnewski AV, Liu Q, Liu J, Redlich CA (2005) Glutathione protects human airway proteins and epithelial cells from isocyanates. Clin Exp Allergy 35:352–357PubMedCrossRef

Titel: Influence of polymorphic metabolic enzymes on biotransformation and effects of diphenylmethane diisocyanate
verfasst von: Margareta Littorin
Saimei Hou
Karin Broberg
Jonas Björk
Susanne Fält
Galbani Abdoulaye
Malgorzata Kalemba
Charlotta Ryk
Staffan Skerfving
Publikationsdatum: 01.02.2008
Verlag: Springer-Verlag
Erschienen in: International Archives of Occupational and Environmental Health / Ausgabe 4/2008
Print ISSN: 0340-0131
Elektronische ISSN: 1432-1246
DOI: https://doi.org/10.1007/s00420-007-0232-x

Springer Medizin

Abstract

Objectives

Methods

Results

Conclusions

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