The GSTP1 Ile105 Val polymorphism modifies the metabolism of toluene di-isocyanate.
BACKGROUND
Toluene di-isocyanate (TDI) is widely used in the production of polyurethane foams and paints. As TDI causes respiratory disease in only a fraction of exposed workers, genetic factors may play a key role in disease susceptibility. Polymorphisms in TDI metabolising genes may affect elimination kinetics, resulting in differences in body retention, and in its turn differences in adverse effects.


OBJECTIVE
To analyze how genotype modifies the associations between (i) TDI in air (2,4-TDI and 2,6-TDI) and its metabolites toluene diamine (TDA; 2,4-TDA and 2,6-TDA) in hydrolyzed urine; and (ii) 2,4-TDA and 2,6-TDA in hydrolyzed plasma and 2,4-TDA and 2,6-TDA in urine.


METHODS
Workers exposed to TDI were analyzed for 2,4-TDI and 2,6-TDI in air (N=70), 2,4-TDA and 2,6-TDA in hydrolyzed urine (N=124) and in plasma (N=128), and genotype: CYP1A1*2A, CYP1A1*2B, GSTA1-52, GSTM1O, GSTM3B, GSTP1 I105V, GSTP1 A114V, GSTT1O, MPO-463, NAT1*3, *4, *10, *11, *14, *15, NAT2*5, *6, *7, and SULT1A1 R213H.


RESULTS
GSTP1 105 strongly modified the relationship between 2,4-TDA in plasma and in urine: ValVal carriers had about twice as steep regression slope than IleIle carriers. A similar pattern was found for 2,6-TDA. CYP1A1*2A, GSTM1, GSTP1, GSTT1, and MPO possibly influenced the relationship between TDA in plasma and urine.


CONCLUSIONS
Our results show, for the first time, genetic modification on the human TDI metabolism. The findings suggest that GSTP1 genotype should be considered when evaluating biomarkers of TDI exposure in urine and plasma. Moreover, the results support earlier findings of GSTP1 105 Val as protective against TDI-related asthma.
Broberg
Karin E
KE
Department of Occupational and Environmental Medicine, Lund University, Lund, Sweden. karin.broberg@med.lu.se
Warholm
Margareta
M
Tinnerberg
Håkan
H
Axmon
Anna
A
Jönsson
Bo A
BA
Sennbro
Carl Johan
CJ
Littorin
Margareta
M
Rannug
Agneta
A
D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics*; D015415:Biomarkers; D005260:Female; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D006801:Humans; D007532:Isoleucine / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010655:Phenylenediamines / Q000097:blood / Q000652:urine; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014051:Toluene 2,4-Diisocyanate / Q000378:metabolism* / Q000493:pharmacokinetics; D014633:Valine / Q000235:genetics*; D055815:Young Adult
D015415:Biomarkers; D010655:Phenylenediamines; D007532:Isoleucine; D014051:Toluene 2,4-Diisocyanate; C026942:2,6-diisocyanatotoluene; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D014633:Valine; C010914:2,4-diaminotoluene