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Hemoglobin and albumin adducts of benzene oxide among workers exposed to high levels of benzene 总被引:3,自引:0,他引:3
Yeowell-O'Connell K; Rothman N; Smith MT; Hayes RB; Li G; Waidyanatha S; Dosemeci M; Zhang L; Yin S; Titenko-Holland N; Rappaport SM 《Carcinogenesis》1998,19(9):1565-1571
Benzene oxide (BO) reacts with cysteinyl residues in hemoglobin (Hb) and
albumin (Alb) to form protein adducts (BO-Hb and BO-Alb), which are
presumed to be specific biomarkers of exposure to benzene. We analyzed
BO-Hb in 43 exposed workers and 42 unexposed controls, and BO-Alb in a
subsample consisting of 19 workers and 19 controls from Shanghai, China, as
part of a larger cross-sectional study of benzene biomarkers. The adducts
were analyzed by gas chromatography-mass spectrometry following reaction of
the protein with trifluoroacetic anhydride and methanesulfonic acid. When
subjects were divided into controls (n = 42) and workers exposed to < or
=31 (n = 21) and >31 p.p.m. (n = 22) benzene, median BO-Hb levels were
32.0, 46.7 and 129 pmol/g globin, respectively (correlation with exposure:
Spearman r = 0.67, P < 0.0001). To our knowledge, these results
represent the first observation in humans that BO-Hb levels are
significantly correlated with benzene exposure. Median BO-Alb levels in
these 3 groups were 103 (n = 19), 351 (n = 7) and 2010 (n = 12) pmol/g Alb,
respectively, also reflecting a significant correlation with exposure
(Spearman r = 0.90, P < 0.0001). The blood dose of BO predicted from
both Hb and Alb adducts was very similar. These results clearly affirm the
use of both Hb and Alb adducts of BO as biomarkers of exposure to high
levels of benzene. As part of our investigation of the background levels of
BO-Hb and BO-Alb found in unexposed persons, we analyzed recombinant human
Hb and Alb for BO adducts. Significant levels of both BO-Hb (19.7 pmol/g)
and BO-Alb (41.9 pmol/g) were detected, suggesting that portions of the
observed background adducts reflect an artifact of the assay, while other
portions are indicative of either unknown exposures or endogenous
production of adducts.
相似文献
2.
Albumin and hemoglobin adducts as biomarkers of exposure to styrene in fiberglass-reinforced-plastics workers 总被引:2,自引:0,他引:2
S. Fustinoni C. Colosio A. Colombi K. Yeowell-O'Connell L. Lastrucci S. M. Rappaport 《International archives of occupational and environmental health》1998,71(1):35-41
Objective: The purpose of this work was to compare levels of styrene-7,8-oxide (SO) adducts of albumin (Alb) and hemoglobin (Hb) with
those of two urinary metabolites of styrene, mandelic acid (MA) and phenylglyoxylic acid (PGA), among workers exposed to styrene
in the reinforced-plastics industry and in unexposed subjects. We also wished to determine whether cigarette smoking influenced
adduct levels among these subjects.
Methods: A group of 22 male workers was selected on basis of an expectedly high level of exposure to styrene, and a group of 15 controls
was selected from hospital blood donors and hospital staff. In the exposed group, MA and PGA were quantified by high-performance
liquid chromatography (HPLC) analysis of urine samples collected prior to the work shift. The SO adducts were cleaved from
cysteine residues by reaction with Raney nickel to give 1-phenylethanol (1-PE) and 2-phenylethanol (2-PE), which, after derivatization,
were measured using gas chromatography-mass spectrometry (GC-MS) in the negative-chemical-ionization (NCI) mode.
Results: The estimated mean levels of MA and MA+PGA were 74 and 159 mg/g creatinine, respectively. Using the levels of urinary metabolites,
an average styrene concentration of about 100 mg/m3 in the workplace air was estimated. The mean levels of 2-PE and 1-PE adducts in exposed workers were 2.84 and 0.60 nmol/g
Alb and 5.44 and 0.43 nmol/g Hb, respectively. When subjects were stratified by level of urinary metabolites [zero (controls),
low-level exposure (MA+PGA ≤159 mg/g creatinine), and high-level exposure (MA+PGA> 159 mg/g creatinine)] and smoking status
(smokers versus nonsmokers), a difference in Alb adduct levels was found among the groups (2-PE P=0.002, 1-PE P=0.052). The difference in 2-PE-Alb levels was related to exposure category, to smoking status, and to their interaction.
Correlations at or near a 0.05 level of significance were observed among the workers (n=22) between individual levels of SO-protein adducts and MA+PGA (2-PE Alb, r=0.54, 2-PE Hb, r=0.40).
Conclusion: Our data suggest that only exposure to relatively high levels of styrene allows a clear relationship to be detected between
styrene exposure and SO adducts, due in part to the effects of cigarette consumption and to the high background levels of
these adducts observed in unexposed subjects.
Received: 3 February 1997 / Accepted: 9 June 1997 相似文献
3.
Protein adducts of 1,4-benzoquinone and benzene oxide among smokers and nonsmokers exposed to benzene in China. 总被引:3,自引:0,他引:3
K Yeowell-O'Connell N Rothman S Waidyanatha M T Smith R B Hayes G Li W E Bechtold M Dosemeci L Zhang S Yin S M Rappaport 《Cancer epidemiology, biomarkers & prevention》2001,10(8):831-838
Hemoglobin (Hb) and albumin (Alb) adducts of the benzene metabolites benzene oxide (BO) and 1,4-benzoquinone (1,4-BQ) were analyzed by gas chromatography-mass spectrometry in 43 exposed workers and 44 unexposed controls from Shanghai, China, as part of a larger cross-sectional study of benzene biomarkers. When subjects were divided into controls (n = 44) and workers exposed to =31 ppm (n = 21) and >31 ppm (n = 22) of benzene, median 1,4-BQ-Alb adducts were 2110, 5850, and 13,800 pmol/g Alb, respectively (correlation with exposure: Spearman r = 0.762; P < 0.0001); median BO-Alb adducts were 106, 417, and 2400 pmol/g Alb, respectively (Spearman r = 0.877; P < 0.0001); and median BO-Hb adducts were 37.1, 50.5, and 136 pmol/g Hb, respectively (Spearman r = 0.757; P < 0.0001). To our knowledge, this is the first observation that adducts of 1,4-BQ are significantly correlated with benzene exposure. When compared on an individual basis, Alb adducts of 1,4-BQ and BO and Hb adducts of BO were highly correlated with each other and with urinary phenol and hydroquinone (P < 0.0001 for all of the comparisons). Although detectable in the assays, Hb adducts of 1,4-BQ and both Hb and Alb adducts of 1,2-BQ produced erratic results and are not reported. Interestingly, cigarette smoking increased Alb adducts of 1,4-BQ but not of BO, suggesting that benzene from cigarette smoke was not the primary contributor to the 1,4-BQ adducts. 相似文献
4.
Protein adducts as dosimeters of human exposure to styrene, styrene-7,8-oxide, and benzene. 总被引:1,自引:0,他引:1
Cysteinyl adducts of hemoglobin (Hb) and albumin (Alb) formed via reactions with reactive species were measured in 48 subjects exposed to styrene (0.24-55.2 ppm) and to styrene-7,8-oxide (SO) (2.65-107 ppb) in a factory producing boats in the USA. Hb and Alb adducts were also investigated among 88 workers exposed to benzene (0-138 ppm) in several Chinese factories. The particular adducts were S-(2-hydroxy-1-phenylethyl) cysteine, from reactions of SO with Alb (designated SO-Alb), and S-phenylcysteine, from reactions of the CYP450 benzene metabolite, benzene oxide (BO), with Hb and Alb (designated BO-Hb and BO-Alb, respectively). The relationships between adduct levels and exposures were investigated in both studies. The estimated slopes varied considerably among the particular combinations of adduct and agent to which the workers were exposed, ranging from 0.815 pmol BO-Hb/g Hb per ppm benzene to 24400 pmol SO-Alb/g Alb per ppm SO. We used these estimated slopes, along with kinetic constants, to predict the systemic doses of SO and BO in humans per mg of styrene, SO or benzene per kg body weight, under certain assumptions. Using RX to signify the particular electrophile (SO or BO) the doses of RX to the blood per unit of dose varied between 2.21 and 4110 nM RX-h/mg agent per kg b.w. The dose of RX to the blood arising from inhalation of SO was almost 2000 times that of styrene (i.e. 4110 vs. 2.21 nM RX/mg agent per kg b.w.) and 430-781 times that of benzene (i.e. 4110 vs. 5.26-9.55 nM RX/mg agent per kg b.w.), depending upon the study. Comparable estimates of the blood dose of BO were obtained from adducts of Hb and Alb and two independent studies of BO-Alb yielded similar dose estimates. These results point to the utility of protein adducts as dosimeters of reactive electrophilic species in occupational studies. Finally, significant levels of background adducts of SO and BO with Hb and Alb were observed among workers, among control subjects and in commercial human proteins. Levels of these background adducts were too great to have arisen from non-occupational exposures to styrene or benzene or from cigarette smoking. 相似文献
5.
Measurement of benzene oxide in the blood of rats following administration of benzene 总被引:2,自引:1,他引:2
Lindstrom AB; Yeowell-O'Connell K; Waidyanatha S; Golding BT; Tornero-Velez R; Rappaport SM 《Carcinogenesis》1997,18(8):1637-1641
Although it is generally assumed that metabolism of benzene proceeds
through an initial step involving oxidation to benzene oxide (BO) by CYP450
in the liver, the production of BO has never been unambiguously confirmed
in animals dosed with benzene. Furthermore, prevailing hypotheses of the
mechanism by which benzene causes cancer have ignored the possibility that
BO might play a direct role, despite the fact that BO is electrophilic,
binds covalently to cell macromolecules and is presumably genotoxic. A
likely reason for this lack of attention to the role of BO in the
carcinogenesis of benzene is the presumption that this epoxide is too
reactive to escape the hepatocyte after it is formed. We employed gas
chromatography-mass spectrometry to measure BO in the blood of F344 rats,
both in vitro and up to 24 h following oral administration of benzene.
Surprisingly, BO was relatively stable in rat blood at 37 degrees C
(estimated half-life = 7.9 min) and, after administering a single dosage of
400 mg benzene/kg body wt, a blood concentration of 90 nM BO (8.5 ng/ml)
was measured for approximately 9 h. Using a published PBPK model we
estimate that approximately 4.3% of the metabolized dose of benzene was
released as BO from the liver into blood. This confirms that BO is, indeed,
formed from metabolism of benzene and is sufficiently stable to be
distributed throughout the body at levels which are likely to be greater
than those of the other electrophilic benzene metabolites.
相似文献
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