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Matsuda T, Terashima I, Matsumoto Y, Yabushita H, Matsui S, Shibutani S
Effective utilization of N-2-ethyl-2 '-deoxyguanosine triphosphate during DNA synthesis catalyzed by mammalian replicative DNA polymerases
Biochemistry (1999) 38:929-935.
Abstract
Acetaldehyde is produced by metabolic oxidation of ethanol after drinking alcoholic beverages. This agent reacts with nucleosides and nucleotides, resulting in the formation of N-2- ethyl-guanine residues. N-2-ethyl-2'-deoxyguanosine (N-2-ethyl- dG) adduct has been detected in the lymphocyte DNA of alcoholic patients [Fang, J. L., and Vaca, C. E. (1997) Carcinogenesis 18, 627-632]. Thus, the nucleotide pool is also expected to be modified by acetaldehyde. N-2-Ethyl-2'-deoxyguanosine triphosphate (N-2-ethyl-dGTP) was chemically synthesized. The utilization of N-2-ethyl-dCTP during DNA synthesis was determined by steady-state kinetic studies. N-2-Ethyl-dGTP was efficiently incorporated opposite template dC in reactions catalyzed by mammalian DNA polymerase alpha and delta. When pol alpha was used, the insertion frequency of N-2-ethyl-dGTP was 400 times less than that of dGTP, but 320 times higher than that of 7,8-dihydro-8-oxo-2'-deoxyguanosine triphosphate (8- oxo-dGTP), an oxidative damaged nucleotide. Using pol delta, the insertion frequency of N-2-ethyl-dGTP was only 37 times less than that of dGTP. The chain extension from dC:N-2-ethyl- dG pair occurred much more rapidly: the extension frequencies for pol alpha and pol delta were only 3.8 times and 6.3 times, respectively, lower than that of dC:dG pair. We also found that N-2-ethyl-dG can be detected in urine samples obtained from healthy volunteers who had abstained from drinking alcohol for 1 week before urine collection. This indicates that humans are exposed constantly to acetaldehyde even without drinking alcoholic beverages. Incorporation of N-2-ethyl-dG adducts into DNA may cause mutations and may be related to the development of alcohol- and acetaldehyde-induced human cancers.
Note
Publication Date: 1999-01-19.
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