title: The GSTP1 Ile105 Val polymorphism modifies the metabolism of toluene di-isocyanate.
abstract: 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.
authors.affiliation: Department of Occupational and Environmental Medicine, Lund University, Lund, Sweden. karin.broberg@med.lu.se
authors.forename: Karin E
authors.initials: KE
authors.lastname: Broberg
authors.forename: Margareta
authors.initials: M
authors.lastname: Warholm
authors.forename: Håkan
authors.initials: H
authors.lastname: Tinnerberg
authors.forename: Anna
authors.initials: A
authors.lastname: Axmon
authors.forename: Bo A
authors.initials: BA
authors.lastname: Jönsson
authors.forename: Carl Johan
authors.initials: CJ
authors.lastname: Sennbro
authors.forename: Margareta
authors.initials: M
authors.lastname: Littorin
authors.forename: Agneta
authors.initials: A
authors.lastname: Rannug
mesh_terms: 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
chemical_list: 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