Influence of polymorphic metabolic enzymes on biotransformation and effects of diphenylmethane diisocyanate.
OBJECTIVE
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.
Department of Occupational and Environmental Medicine, University Hospital, 221 85 Lund, Sweden. Margareta.Littorin@med.lu.se
Margareta
M
Littorin
Saimei
S
Hou
Karin
K
Broberg
Jonas
J
Björk
Susanne
S
Fält
Galbani
G
Abdoulaye
Malgorzata
M
Kalemba
Charlotta
C
Ryk
Staffan
S
Skerfving
D000328:Adult; D000367:Age Factors; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D001711:Biotransformation; D005260:Female; D051549:Glutathione S-Transferase pi / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D017953:Isocyanates / Q000493:pharmacokinetics* / Q000633:toxicity*; D008297:Male; D008875:Middle Aged; D016273:Occupational Exposure / Q000009:adverse effects; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011140:Polyurethanes / Q000493:pharmacokinetics* / Q000633:toxicity*; D012129:Respiratory Function Tests; D012140:Respiratory Tract Diseases / Q000209:etiology / Q000235:genetics; D013997:Time Factors; D001559:Benzhydryl Compounds
D001191:Arylamine N-Acetyltransferase; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D007074:Immunoglobulin G; D017953:Isocyanates; D011140:Polyurethanes; C005969:4,4'-diphenylmethane diisocyanate; D001559:Benzhydryl Compounds; C478900:NAT2 protein, human; C413545:glutathione S-transferase T1; C483009:GSTM3 protein, human; C496556:GSTP1 protein, human