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

Littorin, Margareta; Hou, Sai‐Mei; Broberg, Karin; Björk, Jonas; Fält, Susanne; Abdoulaye, Galbani; Kalemba, Malgorzata; Ryk, Charlotta; Skerfving, Staffan

doi:10.1007/s00420-007-0232-x

Cited by 9 publications

(5 citation statements)

References 53 publications

(63 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The strongest effect was found for GSTP1 105, and thus, GSTP1 114 appeared less important for TDI metabolism, in line with what has been shown for other substrates of GSTP1. In contrast, for 4,4 0 -diphenylmethane di-isocyanate, GSTP1 114 may in particular influence the relation between the 4,4 0 -diphenylmethane di-isocyanate-related amine biomarker in plasma and urine [26].…”

Section: Discussionmentioning

confidence: 89%

The GSTP1 Ile105 Val polymorphism modifies the metabolism of toluene di-isocyanate

Broberg

Warholm²,

Tinnerberg

et al. 2010

Pharmacogenetics and Genomics

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 89%

The GSTP1 Ile105 Val polymorphism modifies the metabolism of toluene di-isocyanate

Broberg

Warholm²,

Tinnerberg

et al. 2010

Pharmacogenetics and Genomics

Self Cite

View full text Add to dashboard Cite

show abstract

“…There is good rationale to explore GST genotype variants in that GST has been shown to modify biotransformation of isocyanates and excretion of metabolic products 164 . Reduced glutathione directly inhibits in vitro binding of diisocyanates with albumin 165 .…”

Section: Genetic Susceptibility Factors For Oamentioning

confidence: 99%

Pathogenesis and Disease Mechanisms of Occupational Asthma

Lummus

Wisnewski

Bernstein

2011

Immunology and Allergy Clinics of North America

View full text Add to dashboard Cite

“…In animal studies, inhalation of isocyanate vapors acutely alters airway fluid GSH levels, while GSH depletion exacerbates MDI's respiratory tract toxicity (Pauluhn 2000a, b). Among occupationally exposed workers, the development of isocyanate asthma, and rate of chemical excretion have been associated with genetic polymorphisms in GSH-dependent enzymes (Broberg et al 2010; Littorin et al 2008; Mapp et al 2002; Piirila et al 2001; Wikman et al 2002). …”

Section: Introductionmentioning

confidence: 99%

Hexamethylene diisocyanate (HDI) vapor reactivity with glutathione and subsequent transfer to human albumin

Wisnewski

Mhike

Hettick

et al. 2013

Toxicology in Vitro

View full text Add to dashboard Cite

INTRODUCTION Airway fluid glutathione (GSH) reactivity with inhaled vapors of diisocyanate, a common occupational allergen, is postulated to be a key step in exposure-induced asthma pathogenesis. METHODS A mixed (vapor/liquid) phase exposure system was used to model the in vivo reactivity of inhaled HDI vapor with GSH in the airway fluid. HDI-GSH reaction products, and their capacity to transfer HDI to human albumin, were characterized through mass spectrometry and serologic assays, using HDI-specific polyclonal rabbit serum. RESULTS HDI vapor exposure of 10 mM GSH solutions resulted in primarily S-linked, bis(GSH)-HDI reaction products. In contrast, lower GSH concentrations (100 μM) resulted in mainly mono(GSH)-HDI conjugates, with varying degrees of HDI hydrolysis, dimerization and/or intra-molecular cyclization, depending upon the presence/absence of H2PO4-/HPO42- and Na+/Cl- ions. The ion composition and GSH concentration of the fluid phase, during HDI vapor exposure, strongly influenced the transfer of HDI from GSH to albumin, as did the pH and duration of the carbamoylating reaction. When carbamoylation was performed overnight at pH 7, twenty-five of albumin's lysines were identified as potential sites of conjugation with partially hydrolyzed HDI. When carbamoylation was performed at pH 9, more rapid (within 3 hours) and extensive modification was observed, including additional lysine sites, intra-molecular cross-linkage with HDI, and novel HDI-GSH conjugation. CONCLUSIONS The data define potential mechanisms by which the levels of GSH, H2PO4-4/HPO42-, and/or other ions (e.g. H+/OH-, Na+, Cl-) affect the reactivity of HDI vapor with self-molecules in solution (e.g. airway fluid), and thus, might influence the clinical response to HDI respiratory tract exposure.

show abstract

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

Abstract: 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.

Cited by 9 publications

References 53 publications

The GSTP1 Ile105 Val polymorphism modifies the metabolism of toluene di-isocyanate

The GSTP1 Ile105 Val polymorphism modifies the metabolism of toluene di-isocyanate

Pathogenesis and Disease Mechanisms of Occupational Asthma

Hexamethylene diisocyanate (HDI) vapor reactivity with glutathione and subsequent transfer to human albumin

Contact Info

Product

Resources

About