Carcinogenesis, Vol 18, 137-147, Copyright © 1997 by Oxford University Press
N Tretyakova, Y Lin, R Sangaiah, PB Upton and JA Swenberg
3,4-Epoxy-1-butene (EB) is the major mutagenic metabolite of butadiene
(BD), an important industrial chemical classified as a probable human
carcinogen. Although the mechanism of carcinogenicity of EB is not known,
its reactions with nucleophilic sites of DNA giving pro- mutagenic lesions
are likely to constitute the early crucial step in multistage
carcinogenesis. This study was conducted to characterize the adducts formed
from reactions of EB with the most nucleophilic DNA nucleobases, adenine
(Ade) and guanine (Gua), as free nucleobases, 2'- deoxyribonucleosides and
constituents of calf thymus DNA (CT DNA) in order to provide insight into
the nature of DNA modification by EB. The adducts were isolated using HPLC
separation coupled with diode array detection (DAD) and structurally
characterized from their electronic, mass- and nuclear magnetic resonance
spectra. Four EB-adenine products were identified as
N-1-(2-hydroxy-3-buten-1-yl) adenine (EB-Ade I), N-1-
(1-hydroxy-3-buten-2-yl) adenine (EB-Ade II), N-3-(2-hydroxy-3-buten-1- yl)
adenine (EB-Ade III) and N-3-(1-hydroxy-3-buten-2-yl) adenine (EB- Ade IV).
Two previously reported guanine adducts: 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 also collected. The purified adducts were used as reference compounds
to detect and quantitate the corresponding adduct species formed in calf
thymus DNA incubated with EB. All six adducts were detected in treated DNA.
The N-7 position of guanine was the most reactive in DNA followed by N-3 of
adenine and N-1 of adenine. The formation of N-1 and N-3-adenine adducts
(EB-Ade I, 1.2 +/- 0.36; EB- Ade II, 0.8 +/- 0.27; EB-Ade III, 2.7 +/-
0.38; EB-Ade IV, 5.9 +/- 0.68 nmol/micromol Ade) in CT DNA was
approximately one-tenth that of EB- guanine adducts (50.7 +/- 2.37 and 47.9
+/- 3.6 nmol/micromol Gua, respectively). The N-1-EB-Ade adducts detected
in this study are likely to be the precursors of previously reported
N6-EB-adenine adducts (Koivisto et al., 1995) through Dimroth
rearrangement. Since BD and EB induce significant numbers of point
mutations at A:T base pairs, the EB- adenine adducts may represent
important lesions involved in BD-induced mutagenesis and carcinogenesis.
ARTICLES
Identification and quantitation of DNA adducts from calf thymus DNA exposed to 3,4-epoxy-1-butene
Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill 27599-7400, USA.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  R. A. Kemper, R. J. Krause, and A. A. Elfarra Metabolism of Butadiene Monoxide by Freshly Isolated Hepatocytes from Mice and Rats: Different Partitioning between Oxidative, Hydrolytic, and Conjugation Pathways Drug Metab. Dispos., June 1, 2001; 29(6): 830 - 836. [Abstract] [Full Text]
|
|
|
|
 |
|
 P. Koivisto, I. Kilpelainen, I. Rasanen, I.-D. Adler, F. Pacchierotti, and K. Peltonen Butadiene diolepoxide- and diepoxybutane-derived DNA adducts at N7-guanine: a high occurrence of diolepoxide-derived adducts in mouse lung after 1,3-butadiene exposure Carcinogenesis, July 1, 1999; 20(7): 1253 - 1259. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. R. Selzer and A. A. Elfarra In vitro reactions of butadiene monoxide with single- and double-stranded DNA: characterization and quantitation of several purine and pyrimidine adducts Carcinogenesis, February 1, 1999; 20(2): 285 - 292. [Abstract] [Full Text] [PDF]
|
|