Inhalation Exposure of Rats and Mice to 1,3-Butadiene Induces N 6 -Adenine Adducts of Epoxybutene Detected by 32 P-Postlabeling and HPLC

Koivisto, Pertti; Adler, I.‐D.; Sorsa, Marja; Peltonen, Kimmo

doi:10.2307/3432840

Cited by 5 publications

(6 citation statements)

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“…35−38 N 6 -HB-dA I and N 6 -HB-dA II adducts have been observed in DNA isolated from several tissues of laboratory mice and rats exposed to BD by inhalation. 39,40 DEB can sequentially react at two sites within the adenine heterocycle to form exocyclic deoxyadenosine lesions: N 6 ,N 6 -(2,3-dihydroxybutan-1,4-diyl)-2′-deoxyadenosine (N 6 ,N 6 -DHB-dA), N 6 -(2-hydroxy-3-hydroxymethylpropan-1,3-diyl)-2′deoxy-adenosine (1,N 6 -γ HMHP-dA), and 1,N 6 -(1-hydroxymethyl-2-hydroxypropan-1,3-diyl)-2′-deoxyadenosine (1,N 6 -α HMHP-dA) (Scheme 1). 33,41,42 HMHP-dA and N 6 ,N 6 -DHB-dA adducts were found in calf thymus DNA treated with DEB, 33 while 1,N 6 -HMHP-dA adducts were also detected in DNA of mice exposed to BD.…”

Section: ■ Introductionmentioning

confidence: 99%

Polymerase Bypass of N⁶-Deoxyadenosine Adducts Derived from Epoxide Metabolites of 1,3-Butadiene

Kotapati

Wickramaratne

Esades

et al. 2015

Chem. Res. Toxicol.

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N 6-(2-Hydroxy-3-buten-1-yl)-2′-deoxyadenosine (N6-HB-dA I) and N6,N6-(2,3-dihydroxybutan-1,4-diyl)-2′-deoxyadenosine (N6,N6-DHB-dA) are exocyclic DNA adducts formed upon alkylation of the N6 position of adenine in DNA by epoxide metabolites of 1,3-butadiene (BD), a common industrial and environmental chemical classified as a human and animal carcinogen. Since the N6-H atom of adenine is required for Watson-Crick hydrogen bonding with thymine, N6-alkylation can prevent adenine from normal pairing with thymine, potentially compromising the accuracy of DNA replication. To evaluate the ability of BD-derived N6-alkyladenine lesions to induce mutations, synthetic oligodeoxynucleotides containing site-specific (S)-N6-HB-dA I and (R,R)-N6,N6-DHB-dA adducts were subjected to in vitro translesion synthesis in the presence of human DNA polymerases β, η, ι, and κ. While (S)-N6-HB-dA I was readily bypassed by all four enzymes, only polymerases η and κ were able to carry out DNA synthesis past (R,R)-N6,N6-DHB-dA. Steady-state kinetic analyses indicated that all four DNA polymerases preferentially incorporated the correct base (T) opposite (S)-N6-HB-dA I. In contrast, hPol β was completely blocked by (R,R)-N6,N6-DHB-dA, while hPol η and κ inserted A, G, C, or T opposite the adduct with similar frequency. HPLC-ESI-MS/MS analysis of primer extension products confirmed that while translesion synthesis past (S)-N6-HB-dA I was mostly error-free, replication of DNA containing (R,R)-N6,N6-DHB-dA induced significant numbers of A, C, and G insertions and small deletions. These results indicate that singly substituted (S)-N6-HB-dA I lesions are not miscoding, but exocyclic (R,R)-N6,N6-DHB-dA adducts are strongly mispairing, probably due to their inability to form stable Watson-Crick pairs with dT.

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Section: ■ Introductionmentioning

confidence: 99%

Polymerase Bypass of N⁶-Deoxyadenosine Adducts Derived from Epoxide Metabolites of 1,3-Butadiene

Kotapati

Wickramaratne

Esades

et al. 2015

Chem. Res. Toxicol.

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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 ( − ) and DEB (), N-1, N-3, N 6 , and N-7 adenine adducts of EB ( 30 , 31 , − , and N-3, N 6 , N-7, and N-9 adenine adducts of DEB ( − ) and N -3-thymidine adducts of EB () have been characterized. LC/ESI + /MS/MS ( , ) and 32 P-postlabeling ( 27 , 28 , 34 , 35 , 37 , − 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.

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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“…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: 97%

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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Inhalation Exposure of Rats and Mice to 1,3-Butadiene Induces N 6 -Adenine Adducts of Epoxybutene Detected by 32 P-Postlabeling and HPLC

Cited by 5 publications

References 2 publications

Polymerase Bypass of N⁶-Deoxyadenosine Adducts Derived from Epoxide Metabolites of 1,3-Butadiene

Polymerase Bypass of N⁶-Deoxyadenosine Adducts Derived from Epoxide Metabolites of 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

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Inhalation Exposure of Rats and Mice to 1,3-Butadiene Induces N 6 -Adenine Adducts of Epoxybutene Detected by 32 P-Postlabeling and HPLC

Cited by 5 publications

References 2 publications

Polymerase Bypass of N6-Deoxyadenosine Adducts Derived from Epoxide Metabolites of 1,3-Butadiene

Polymerase Bypass of N6-Deoxyadenosine Adducts Derived from Epoxide Metabolites of 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

Contact Info

Product

Resources

About

Polymerase Bypass of N⁶-Deoxyadenosine Adducts Derived from Epoxide Metabolites of 1,3-Butadiene

Polymerase Bypass of N⁶-Deoxyadenosine Adducts Derived from Epoxide Metabolites of 1,3-Butadiene