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

  • Margareta Littorin
  • Saimei Hou
  • Karin Broberg
  • Jonas Björk
  • Susanne Fält
  • Galbani Abdoulaye
  • Malgorzata Kalemba
  • Charlotta Ryk
  • Staffan Skerfving
Original Article

DOI: 10.1007/s00420-007-0232-x

Cite this article as:
Littorin, M., Hou, S., Broberg, K. et al. Int Arch Occup Environ Health (2008) 81: 429. doi:10.1007/s00420-007-0232-x

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 GSTP1105 isoleucine/isoleucine and GSTP1114 alanine/alanine genotypes showed higher levels of U-MDX than the other genotypes and the GSTP1114 genotype modified the P-MDX/U-MDX relationship. GSTP1105 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.

Keywords

AirwaysBiomarkersGenesIsocyanatesPolymorphism

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

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Margareta Littorin
    • 1
  • Saimei Hou
    • 2
  • Karin Broberg
    • 1
  • Jonas Björk
    • 1
  • Susanne Fält
    • 2
  • Galbani Abdoulaye
    • 2
  • Malgorzata Kalemba
    • 1
  • Charlotta Ryk
    • 2
  • Staffan Skerfving
    • 1
  1. 1.Department of Occupational and Environmental MedicineUniversity HospitalLundSweden
  2. 2.Environmental Medicine Unit, Department of Biosciences, Karolinska InstituteCNT/NOVUM HuddingeSweden