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

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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.

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Abbreviations

Abce:

Absorbance

A:

Alanine

Ab:

Absence, absent

Adj:

Adjusted

CI:

Confidence interval

FEV1 :

Forced expiratory volume in one second

FVC:

Forced vital capacity

GSH:

Glutathione

GST:

Glutathione S-transferase

HDI:

Hexamethylene diisocyanate

I:

Isoleucine

Im:

Intermediate acetylator, rapid/slow heterozygote

kU:

Kilo units

LQ:

Limit of quantification

MDA:

4,4′-methylene dianiline = 4,4′-diaminodiphenylmethane

MDI:

4,4′diphenylmethane diisocyanate

MDX:

Compound determined as MDA after hydrolysis

NAT:

N-acetyltransferase

OR:

Odds ratio

P:

Plasma

Pr:

Presence, present

PUR:

Polyurethane

R:

Rapid acetylator, homozygote

S:

Serum

Sl:

Slow acetylator, homozygote

U:

Urine

V:

Valine

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Acknowledgments

The study was supported by the Swedish Foundation for Health Care Sciences and Allergy Research, the Swedish Council for Work Life Research, the Swedish Medical Research Council, the Swedish Council for Working Life and Social Research, the Medical Faculty of Lund University, and the county councils of southern Sweden. The determinations of metabolites were made by Dr. Gunnar Skarping. The antibody analyses were conducted by Dr. Hans Welinder. Skilful assistance was given by Ms. Pia Aprea, Ms. Inger Bensryd, Ms. Birgitta Björk, Ms. Cecilia Gustavsson, Ms. Anita Nilsson, Ms. Helen Ottosson, and Ms. Karin Paulsson. We thank the workers and the management of the firm, as well as the occupational health service, for all their support.

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Authors and Affiliations

  1. Department of Occupational and Environmental Medicine, University Hospital, 221 85, Lund, Sweden

    Margareta Littorin, Karin Broberg, Jonas Björk, Malgorzata Kalemba & Staffan Skerfving

  2. Environmental Medicine Unit, Department of Biosciences, Karolinska Institute, CNT/NOVUM, 141 57, Huddinge, Sweden

    Saimei Hou, Susanne Fält, Galbani Abdoulaye & Charlotta Ryk

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  1. Margareta Littorin
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  2. Saimei Hou
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Correspondence to Margareta Littorin.

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Littorin, M., Hou, S., Broberg, K. et al. Influence of polymorphic metabolic enzymes on biotransformation and effects of diphenylmethane diisocyanate. Int Arch Occup Environ Health 81, 429–441 (2008). https://doi.org/10.1007/s00420-007-0232-x

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