Alkylation of DNA and proteins in mice exposed to vinyl chloride

doi:10.1016/0006-291X(77)90720-3

Biochemical and Biophysical Research Communications

Volume 76, Issue 2, 23 May 1977, Pages 259-266

https://doi.org/10.1016/0006-291X(77)90720-3 Get rights and content

Abstract

Experiments with mice show that the pre-carcinogen vinyl chloride is metabolically converted to a short-lived alkylating intermediate which introduces the 2-oxoethyl group onto nucleophilic sites in DNA and proteins. The absolute and relative amounts of alkylated products support the hypothesis that the main reactive metabolite is chloroethylene oxide.

References (18)

S. Osterman-Golkar et al.
Mutat. Res
(1976)
H.M. Bolt et al.
Lancet
(1975)
U. Rannug et al.
Chem.-Biol.Interact
(1976)
S. Osterman-Golkar et al.
Radiat. Bot
(1970)
L. Ehrenberg et al.
Radiat. Bot
(1974)
S. Hussain et al.
Chem. Biol. Interact
(1976)
J.R. Barrio et al.
Biochem. Biophys. Res. Commun
(1972)
R. Göthe et al.
Ambio
(1974)
A. Zilkha et al.
J. Org. Chem
(1963)

There are more references available in the full text version of this article.

Cited by (126)

Literature review and evaluation of biomarkers, matrices and analytical methods for chemicals selected in the research program Human Biomonitoring for the European Union (HBM4EU)
2022, Environment International
Citation Excerpt :
This includes the formation of adducts of xenobiotics with biomolecules, such as the hemoglobin (Hb)-, albumin-, and DNA-adducts (Henderson et al. 1989). A quantitative relationship between DNA-adducts and hemoglobin adducts in mice was reported for ethylene oxide (Ehrenberg et al. 1974) or vinyl chloride (Osterman-Golkar et al. 1976). 2-Acetylaminofluorene (Pereira et al. 1981) reacted with Hb and DNA of the target organ in a dose-dependent manner.
Humans are potentially exposed to a large amount of chemicals present in the environment and in the workplace. In the European Human Biomonitoring initiative (Human Biomonitoring for the European Union = HBM4EU), acrylamide, mycotoxins (aflatoxin B1, deoxynivalenol, fumonisin B1), diisocyanates (4,4′-methylenediphenyl diisocyanate, 2,4- and 2,6-toluene diisocyanate), and pyrethroids were included among the prioritized chemicals of concern for human health. For the present literature review, the analytical methods used in worldwide biomonitoring studies for these compounds were collected and presented in comprehensive tables, including the following parameter: determined biomarker, matrix, sample amount, work-up procedure, available laboratory quality assurance and quality assessment information, analytical techniques, and limit of detection. Based on the data presented in these tables, the most suitable methods were recommended. According to the paradigm of biomonitoring, the information about two different biomarkers of exposure was evaluated: a) internal dose = parent compounds and metabolites in urine and blood; and b) the biologically effective = dose measured as blood protein adducts. Urine was the preferred matrix used for deoxynivalenol, fumonisin B1, and pyrethroids (biomarkers of internal dose). Markers of the biological effective dose were determined as hemoglobin adducts for diisocyanates and acrylamide, and as serum-albumin-adducts of aflatoxin B1 and diisocyanates. The analyses and quantitation of the protein adducts in blood or the metabolites in urine were mostly performed with LC-MS/MS or GC-MS in the presence of isotope-labeled internal standards. This review also addresses the critical aspects of the application, use and selection of biomarkers. For future biomonitoring studies, a more comprehensive approach is discussed to broaden the selection of compounds.
Direct quantitation of hydroxyethylvaline in hemoglobin by liquid chromatography/positive electrospray tandem mass spectrometry
2012, Journal of Chromatography A
Citation Excerpt :
Therefore, reliable, simple, and accurate methods for quantifying HEVal are key to provision of internal dose information for such studies. Very early methods to quantify these alkylated hemoglobin adducts (such as hydroxyethylated hemoglobin adducts) from animal exposures involved the use of radioactively labeled alkylating agents, which, upon adduct isolation and subsequent radioactivity counting, were quantified by virtue of the radioactive label [6–8]. This traditional procedure is expensive because it requires the synthesis of radiolabeled reactive chemicals (or active chemical metabolites) and it necessitates special precautions for proper radiochemical handling of samples.
Hemoglobin adducts are often used as biomarkers of exposure to reactive chemicals in toxicology studies. Therefore rapid, sensitive, accurate, and reproducible methods for quantifying these globin adducts are key to evaluate test material dosimetry. A new, simple, fast, and sensitive LC/ESI-MS/MS methodology has been developed and validated for the quantitation of hydroxyethylvaline (HEVal) in globin samples isolated from rats, both control and exposed to ethylene. Globin samples were first hydrolyzed to amino acids (including HEVal), followed by direct LC/ESI-MS/MS analysis. The lower limit of quantitation was 0.0095 ng/mL (0.026 pmol/mg globin). Typical calibration curves obtained over three days were linear over a concentration range from 0.0095 to 9.524 ng/mL, with correlation coefficient R² > 0.999. The intra-day assay precision RSD values for all QC samples were ≤11.2%, with accuracy values ranging from 90.6 to 105%. The inter-day assay precision RSD values for all QC samples were ≤8.73%, with accuracy values ranging from 89.3 to 104.5%. The stability of HEVal in three freeze–thaw cycles over 48 h and at room temperature over 24 h was also evaluated, and the measured concentrations of HEVal were compared to the nominal values, with accuracy ranging from 94.8% to 109%. In conclusion, this method provides results comparable to those obtained using the traditional and complex Edman degradation phenylthiohydantoin-related quantitation method, but is much simpler and faster to conduct.
Detection and identification of carcinogen-peptide adducts by nanoelectrospray tandem mass spectrometry
1998, Journal of the American Society for Mass Spectrometry
Nanoelectrospray (nanoES) tandem mass spectrometry was used to examine covalently modified peptides in crude enzymatic digests of human serum albumin (HSA) that had been exposed to either benzo[a]pyrene diol epoxide (B[a]PDE, 1), chrysene diol epoxide (CDE, 2), 5-methylchrysene diol epoxide (5MeCDE, 3), or benzo[g]chrysene diol epoxide (B[g]CDE, 4). The low flow rates of nanoES (∼20 nL/min) allowed several MS/MS experiments to be optimized and performed on a single sample with very little sample consumption (∼30 min analysis time/μL sample). Initially, nanoES was compared with conventional LC/MS/MS analysis of carcinogen-peptide adducts. For example, nanoES analysis of an unseparated digest of B[a]PDE-treated serum albumin revealed the same peptides (RRHPY and RRHPY-FYAPE) that were previously shown, by LC/MS/MS, to be adducted with B[a]PDE. In addition, nanoES could detect unstable peptide adducts that might not otherwise have been directly observable. Finally, nanoES was shown to be an effective way to screen mixtures of modified and unmodified peptides for which no chromatographic information is available.
Chromatographic and electrophoretic methods for modified hemoglobins
1997, Journal of Chromatography B: Biomedical Applications
The discovery of the clinically important glycohemoglobin adducts and their relation to diabetes mellitus have greatly stimulated the study of other minor post-translational modifications of hemoglobin. Chromatographic and electrophoretic procedures have played an important role in these studies. Today several hemoglobin adducts are known and the formation of adducts with glucose, phosphorylated carbohydrates, urea/cyanate, aspirin, vitamins, acetaldehyde, penicillin and acetyl CoA have been described. Furthermore, new adducts, such as those observed using hemoglobin as a biochemical marker monitoring environmental, occupational and lifestyle exposures to reactive toxic chemicals are constantly being reported. This review deals with chromatographic and electrophoretic separation methods available for the study of non-enzymatic post-translational modifications of hemoglobin. Suitability, perspectives and biomedical applications are discussed.
Vinyl chloride mechanistic data and risk assessment: DNA reactivity and cross-species quantitative risk extrapolation
1996, Pharmacology and Therapeutics
Vinyl chloride produced several tumor types among species. Angiosarcoma of the liver is found in all tested species, including humans with occupational exposures. Vinyl chloride is biotransformed by CYP2E1 to DNA-reactive chloroethylene oxide producing cyclic etheno adducts, which are mutagenic. The dose-response for angiosarcoma of the liver formation in rodents is supralinear, which is consistent with saturation of metabolic activation, and the tumor rate in humans at occupational exposure levels is similar to that for equivalent exposures in rodents.
Genetic toxicology of vinyl chloride-a review
1995, Mutation Research/Reviews in Genetic Toxicology
Vinyl chloride (VC) is a colorless gas with a mild, sweet odor. It is extensively used in the production of vinyl chloride polymer, copolymer resin, packaging materials, wire and cable coatings as well as in industrial and laboratory intermediates. It is toxic and also carcinogenic in experimental animals. The wide human exposure to this compound in different industries throughout the world causes great concern for human health. In the present review an attempt has been made to evaluate and update the genotoxic effects of vinyl chloride based on the available literature.

View all citing articles on Scopus

View full text

Alkylation of DNA and proteins in mice exposed to vinyl chloride

Abstract

Mutat. Res

Lancet

Chem.-Biol.Interact

Radiat. Bot

Radiat. Bot

Chem. Biol. Interact

Biochem. Biophys. Res. Commun

Ambio

J. Org. Chem