Macromolecular adducts of butadiene

Tretyakova, Natalia; Lin, Yu Pang; Upton, Patricia B.; Sangaiah, R.; Swenberg, James A.

doi:10.1016/0300-483x(96)03429-4

Cited by 44 publications

(20 citation statements)

References 9 publications

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“…Numerous DNA adducts of BD, mainly with guanine and adenine, have been reported in the literature. The N-7 guanine adducts of EB (24)(25)(26)(27)(28)(29)(30)(31) and DEB (32), N-1, N-3, N 6 , and N-7 adenine adducts of EB (30,31,(33)(34)(35), and N-3, N 6 , N-7, and N-9 adenine adducts of DEB (36)(37)(38) and N-3-thymidine adducts of EB (39) have been characterized. LC/ESI + /MS/MS (40,41) and 32 P-postlabeling (27,28,34,35,37,(42)(43)(44)(45) combined with chromatographic separation have been used to characterize and/or quantitate the adducts formed in vitro by EB and DEB.…”

Section: Introductionmentioning

confidence: 99%

Molecular Dosimetry of N-7 Guanine Adduct Formation in Mice and Rats Exposed to 1,3-Butadiene

Koç

Tretyakova

Walker

et al. 1999

Chem. Res. Toxicol.

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126

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1,3-Butadiene (BD) is a high-volume chemical used in the production of rubber and plastic. BD is a potent carcinogen in mice and a much weaker carcinogen in rats, and has been classified as a probable human carcinogen. Upon metabolic activation in vivo, it forms DNA-reactive metabolites, 1,2-epoxy-3-butene (EB), 1,2:3, 4-diepoxybutane (DEB), and 3,4-epoxy-1,2-butanediol (EBD). The molecular dosimetry of N-7 guanine adduct formation by these metabolites of BD in liver, lung, and kidney of B6C3F1 mice and F344 rats exposed to 0, 20, 62.5, or 625 ppm BD was studied. The adducts, racemic and meso forms of N-7-(2,3,4-trihydroxybut-1-yl)guanine (THB-Gua), N-7-(2-hydroxy-3-buten-1-yl)guanine (EB-Gua I), and N-7-(1-hydroxy-3-buten-2-yl)guanine (EB-Gua II), were isolated from DNA by neutral thermal hydrolysis, desalted on solid-phase extraction cartridges, and quantitated by LC/ESI(+)/MS/MS. The number of adducts per 10(6) normal guanine bases for a given adduct was higher in mice than rats exposed to 625 ppm BD, but generally similar at lower levels of exposure. The THB-Gua adducts were the most abundant (6-27 times higher than EB-Gua) and exhibited a nonlinear exposure-response relationship. In rats, the exposure-response curves for the formation of THB-Gua adducts reached a plateau after 62.5 ppm, suggesting saturation of metabolic activation. The number of THB-Gua adducts continued to increase in mice between 62.5 and 625 ppm BD. In contrast, the less common EB-Gua adducts had a linear exposure-response relationship in both species. Combining the information from this study with previous data on BD metabolism, we were able to estimate the number of THB-Gua that resulted from DEB and EBD, and conclude that most of the THB-Gua is formed from EBD. We hypothesize that most of the EBD arises from the immediate conversion of DEB to EBD within the endoplasmic reticulum. This study highlights the need for measurements of the levels of EBD in tissues of rats and mice and for the development of a unique biomarker for DEB that is available for binding to DNA.

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Section: Introductionmentioning

confidence: 99%

Molecular Dosimetry of N-7 Guanine Adduct Formation in Mice and Rats Exposed to 1,3-Butadiene

Koç

Tretyakova

Walker

et al. 1999

Chem. Res. Toxicol.

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126

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“…DNA adducts have been characterized at the N7-position of guanine (Citti et al 1984;Tretyakova et al 1997c;Koivisto et al 1998), N3-position of thymidine (Selzer and Elfarra 1997) and the N1-, N3-and N 6 -positions of adenine (Leuratti et al 1994;Neagu et al 1994;Tretyakova et al 1996;Tretyakova et al 1997a,b;Tretyakova et al 1998;Koivisto et al 1996). Multiple DNA adducts are formed at each of the above positions by the three epoxides, EB, EBD and DEB ( Figure 6).…”

Section: Dna Adductsmentioning

confidence: 99%

Linking Pharmacokinetics and Biomarker Data to Mechanism of Action in Risk Assessment

Swenberg

Gorgeiva

Ham

et al. 2002

Human and Ecological Risk Assessment: An International Journal

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Incorporating information on metabolism, pharmacokinetics, and DNA and protein biomarkers provides a means to integrate these important factors into the risk assessment process. Such data are useful for species to species extrapolation, high-to low-dose extrapolation and PBPK modeling. In addition, these data are critical for understanding the mode of action for chemical carcinogens. Through the use of mass spectrometry, stable isotopes can be used to unequivocally demonstrate pathways of formation of biomarkers and relationships between exogenous and endogenous processes. This paper reviews what has been learned for two carcinogens, vinyl chloride and butadiene. It is clear that such data play major roles in improving the understanding of how chemicals cause cancer, extending the range of data on exposure-response relationships, and examining interspecies differences and inter-individual differences that may affect susceptibility. As such, it is also clear that these data play a critical role in improving the accuracy of risk assessments.

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“…The formation of stable adducts of both the monoepoxide and monoepoxide diol metabolites of butadiene with the N-terminal valine of hemoglobin has been documented in both experimental animals and humans exposed to butadiene (Albrecht et al, 1993;Osterman-Golkar et al, 1993Neumann et al, 1995;Sorsa et al, 1996;Tretyakova et al, 1996;Pérez et al, 1997;J. A. Swenberg, personal communication, 1998).…”

Section: Toxicokinetics and Metabolismmentioning

confidence: 99%

1,3-Butadiene: Exposure Estimation, Hazard Characterization, and Exposure-Response Analysis

Hughes

Walker

et al. 2003

Journal of Toxicology and Environmental Health, Part B

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1,3-Butadiene has been assessed as a Priority Substance under the Canadian Environmental Protection Act. The general population in Canada is exposed to 1,3-butadiene primarily through ambient air. Inhaled 1,3-butadiene is carcinogenic in both mice and rats, inducing tumors at multiple sites at all concentrations tested in all identified studies. In addition, 1,3-butadiene is genotoxic in both somatic and germ cells of rodents. It also induces adverse effects in the reproductive organs of female mice at relatively low concentrations. The greater sensitivity in mice than in rats to induction of these effects by 1,3-butadiene is likely related to species differences in metabolism to active epoxide metabolites. Exposure to 1,3-butadiene in the occupational environment has been associated with the induction of leukemia; there is also some limited evidence that 1,3-butadiene is genotoxic in exposed workers. Therefore, in view of the weight of evidence of available epidemiological and toxicological data, 1,3-butadiene is considered highly likely to be carcinogenic, and likely to be genotoxic, in humans. Estimates of the potency of butadiene to induce cancer have been derived on the basis of both epidemiological investigation and bioassays in mice and rats. Potencies to induce ovarian effects have been estimated on the basis of studies in mice. Uncertainties have been delineated, and, while there are clear species differences in metabolism, estimates of potency to induce effects are considered justifiably conservative in view of the likely variability in metabolism across the population related to genetic polymorphism for enzymes for the critical metabolic pathway.

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Macromolecular adducts of butadiene

Cited by 44 publications

References 9 publications

Molecular Dosimetry of N-7 Guanine Adduct Formation in Mice and Rats Exposed to 1,3-Butadiene

Molecular Dosimetry of N-7 Guanine Adduct Formation in Mice and Rats Exposed to 1,3-Butadiene

Linking Pharmacokinetics and Biomarker Data to Mechanism of Action in Risk Assessment

1,3-Butadiene: Exposure Estimation, Hazard Characterization, and Exposure-Response Analysis

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