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- Kåredal, Monica, et al.
(författare)
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Determination of hexahydrophthalic anhydride adducts to human serum albumin
- 2003
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Ingår i: Biomarkers. - : Informa UK Limited. - 1366-5804 .- 1354-750X. ; 8:5, s. 343-359
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Tidskriftsartikel (refereegranskat)abstract
- Hexahydrophthalic anhydride (HHPA) is a highly sensitizing industrial chemical that is known to covalently bind to endogenous proteins. The aim of this study was to determine the binding sites of HHPA to human serum albumin (HSA). Conjugates between HSA and HHPA, at two different molar ratios, were synthesized under physiological conditions. The conjugates were digested with trypsin and Pronase E to obtain specific peptides and amino acids, which were separated by liquid chromatography (LC). Fractions containing modified peptides were detected through quantification of hydrolysable HHPA using LC coupled to a triple quadrupole mass spectrometer with electrospray ionization. Modified residues in albumin were identified by sequence analyses using nanoelectrospray quadrupole time-of-flight mass spectrometry. A total of 36 HHPA adducts were found in the HSA - HHPA conjugate with 10 times molar excess of added HHPA. In the conjugate with a molar ratio of 1: 0.1 of added HHPA, seven HHPA adducts were found bound to Lys(137) (domain IB), Lys(190), Lys(199) and Lys(212) (domain IIA), Lys(351) (domain IIB), and Lys(432) and Lys(436) (domain IIIA). Moreover, several of these adducted albumin peptides were detected in nasal lavage fluid from one volunteer exposed to HHPA. The binding sites of HHPA to HSA have been determined, thus identifying potential allergenic chemical structures. This knowledge generates the possibility of developing methods for the biological monitoring of HHPA exposure by analysing tryptic peptides including these binding sites.
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- Lindahl, Mats, 1957-, et al.
(författare)
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Nasal lavage fluid and proteomics as means to identify the effects of the irritating epoxy chemical dimethylbenzylamine
- 2004
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Ingår i: Biomarkers. - : Informa UK Limited. - 1354-750X .- 1366-5804. ; 9:1, s. 56-70
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Tidskriftsartikel (refereegranskat)abstract
- The aims of this study were to describe the changes in the nasal lavage fluid (NLF) protein pattern after exposure to the irritating epoxy chemical dimethylbenzylamine (DMBA) and to identify the affected proteins using a proteomic approach. The protein patterns of NLF from six healthy subjects and eight epoxy workers with airway irritation were analysed using two-dimensional gel electrophoresis (2-DE) before and after exposure to 100 μg m-3 DMBA for 2 h in an exposure chamber. NLF proteins were identified by (i) comparison with a 2-DE NLF reference database, (ii) N-terminal amino acid sequencing, and (iii) mass spectrometry. In NLF from healthy subjects, the levels of immunoglobulin A increased and the levels of Clara cell protein 16 (CC16) decreased after chamber exposure, while in NLF from epoxy workers, α2-macroglobulin and caeruloplasmin increased. Two previously unidentified proteins decreased in NLF from epoxy workers after exposure, these were identified as statherin and calgranulin B. In addition, the subjects who developed high counts of eosinophils in their nasal mucosa after chamber exposure had significantly lower levels of immunoglobulin-binding factor (IgBF) before exposure than subjects with low eosinophil infiltration. These results show that short-term exposure to DMBA causes distinct changes in NLF proteins. Moreover, three proteins that have previously not been associated with upper airway irritation were identified: statherin, calgranulin B and IgBF. Further studies are needed to investigate whether these proteins may be used as biomarkers of airway irritation and to give new insight into the ways in which occupational exposure to irritants causes inflammation of the airways.
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- Sennbro, Carl Johan, et al.
(författare)
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Development, validation and characterization of an analytical method for the quantification of hydrolysable urinary metabolites and plasma protein adducts of 2,4-and 2,6-toluene diisocyanate, 1,5-naphthalene diisocyanate and 4,4 '-methylenediphenyl diisocyanate
- 2003
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Ingår i: Biomarkers. - : Informa UK Limited. - 1366-5804 .- 1354-750X. ; 8:3-4, s. 204-217
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Tidskriftsartikel (refereegranskat)abstract
- Occupational exposure to diisocyanates within the plastic industry causes irritation and disorders in the airway. The aim of this study was to develop, validate and characterize a method for the determination of 2,4-toluenediamine (2,4-TDA), 2,6-toluenediamine (2,6-TDA), 1,5-diaminonaphthalene (1,5-NDA) and 4,4'-methylenedianiline (4,4'-MDA) in hydrolysed urine and plasma, and to study the correlation between the plasma and urinary levels of these potential biomarkers of 2,4-toluene diisocyanate (2,4-TDI), 2,6-toluene diisocyanate (2,6-TDI), 1,5-naphthalene diisocyanate (1,5-NDI) and 4,4'-methylenediphenyl diisocyanate (4,4'-MDI), respectively. Samples were hydrolysed with 0.3 M NaOH at 100degreesC for 24 h. The diamines were extracted, derivatized with pentafluoropropionic acid anhydride, and quantified by selected ion monitoring on gas chromatography-mass spectrometry. The repeatability and reproducibility of the method were 7-18% and 7-19%, respectively. Dialysis experiments showed that the metabolites of 2,4-TDI, 2,6-TDI, 1,5-NDI and 4,4'-MDI in plasma were exclusively protein adducts. No free diamines were found in urine, indicating that all diisocyanate-related metabolites were in a conjugated form. For each diisocyanate-related biomarker, there were strongly significant correlations (p < 0.001) between individual levels of metabolites in plasma and urine, with Spearman's rank correlation coefficient (r(s)) values of 0.74-0.90. The methods presented here will be valuable for the development of biological monitoring methods for diisocyanates.
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- Smits, KM, et al.
(författare)
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Interaction between smoking, GSTM1 deletion and colorectal cancer: results from the GSEC study
- 2003
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Ingår i: Biomarkers. - : Informa UK Limited. - 1366-5804 .- 1354-750X. ; 8:3-4, s. 299-310
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Tidskriftsartikel (refereegranskat)abstract
- Cigarette smoking has inconsistently been associated with an increased risk of colorectal cancer. One of the enzymes responsible for the detoxification of the carcinogenic compounds present in tobacco smoke is glutathione S-transferase-mu (GST-mu). The gene that codes for this enzyme is GSTM1. In this study, we evaluated the associations and interaction between GSTM1 deletion, smoking behaviour and the development of colorectal cancer. We performed a pooled analysis within the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens (GSEC). We selected six studies on colorectal cancer, including 1130 cases and 2519 controls, and restricted our analyses to Caucasians because the number of patients from other races was too limited. In addition we performed a meta-analysis including the studies from the GSEC database and other studies identified on MEDLINE on the same subject. The prevalence of the GSTM1 null genotype was within the range reported in other studies: 51.8% of the cases had the GSTM1 null genotype versus 56.6% of the controls. No significant association between the GSTM1 null genotype and colorectal cancer was found (odds ratio 0.92, 95% confidence interval 0.73-1.14). Our results suggest a possible positive association between lack of the GST-mu enzyme and colorectal cancer for non-smoking women (odds ratio 1.47, 95% confidence interval 0.80-2.70). There was no interaction between the effects of smoking and GSTM1 genotype on colorectal cancer risk in men and women (chi(2) = 0.007, p = 0.97). Our findings do not support an association between the GSTM1 null genotype and colorectal cancer. In addition, we did not find any modification of the smoking-induced colorectal cancer risk by GSTM1 genotype.
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