PMID- 9250412
OWN - NLM
STAT- MEDLINE
DCOM- 19971202
LR  - 20181016
IS  - 0893-228X (Print)
IS  - 0893-228X (Linking)
VI  - 10
IP  - 7
DP  - 1997 Jul
TI  - Synthesis, characterization, and in vitro quantitation of N-7-guanine adducts of 
      diepoxybutane.
PG  - 779-85
AB  - Diepoxybutane (DEB) is an important metabolite of 1,3-butadiene (BD), a 
      high-volume industrial chemical classified as a probable human carcinogen. Rodent 
      inhalation studies show strikingly high sensitivity of mice to carcinogenic 
      effects of butadiene compared to rats, which has been linked to differences in 
      metabolism. Both species convert BD to 3,4-epoxy-1-butene (EB), but mice further 
      oxidize a significantly greater part of EB to DEB. DEB is a potent bifunctional 
      genotoxic agent which is 100-fold more mutagenic than EB and is likely to be 
      involved in BD-induced carcinogenesis. Identification of specific BD-induced DNA 
      adducts is critical to understanding the mechanism of its biological activity. We 
      have previously described reactions of EB with guanine and adenine as 
      nucleobases, nucleosides, and constituents of DNA. In this work, DEB-induced 
      guanine adducts were isolated and structurally characterized by UV spectroscopy, 
      mass spectrometry, and nuclear magnetic resonance. When guanosine was reacted 
      with DEB in glacial acetic acid followed by hydrolysis in hydrochloric acid, 
      three products were isolated: N-7-(2',3',4'-trihydroxybut-1'-yl)guanine (DEB-Gua 
      I, major adduct), N-7-(2',4'-dihydroxy-3'-chlorobut-1'-yl)guanine (DEB-Gua II), 
      and N-7-(2',3'-dihydroxy-4'-acetoxybut-1'-yl)guanine (DEB-Gua III). We suggest 
      initial formation of the N-7-(2'-hydroxy-3',4'-epoxybut-1'-yl)guanine 
      intermediate followed by nucleophilic substitution at the 3',4'-epoxy ring with 
      hydroxide, chloride, or acetate anions to give DEB-Gua I, II, or III, 
      respectively. DEB-Gua I and the epoxy intermediate were also isolated from 
      hydrolysates of DEB-exposed calf thymus DNA (CT DNA). N-7-Guanine adducts are 
      known to undergo spontaneous and enzymatic depurination producing apurinic sites. 
      If not repaired before DNA replication, apurinic sites can give rise to mutations 
      and ultimately cancer. The extent of alkylation at the N-7 of guanine in 
      DEB-exposed DNA (58.7 +/- 1.1 adducts/10(3) normal guanines) was similar to that 
      previously reported for CT DNA exposed to EB at the same molar ratio. Since EB 
      and DEB appear to induce comparable levels of overall DNA alkylation at the 
      conditions applied in this work, other factors, such as formation of DNA 
      cross-links by DEB but not EB or differences in repair of EB and DEB adducts, may 
      be responsible for the differences in mutagenicity.
FAU - Tretyakova NYu
AU  - Tretyakova NYu
AD  - Department of Environmental Sciences and Engineering, University of North 
      Carolina, Chapel Hill 27599-7400, USA.
FAU - Sangaiah, R
AU  - Sangaiah R
FAU - Yen, T Y
AU  - Yen TY
FAU - Swenberg, J A
AU  - Swenberg JA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Chem Res Toxicol
JT  - Chemical research in toxicology
JID - 8807448
RN  - 0 (Carcinogens)
RN  - 0 (Epoxy Compounds)
RN  - 12133JR80S (Guanosine)
RN  - 5Z93L87A1R (Guanine)
RN  - 60OB65YNAB (diepoxybutane)
RN  - 9007-49-2 (DNA)
SB  - IM
MH  - Carcinogens/*chemical synthesis/chemistry
MH  - Chromatography, High Pressure Liquid
MH  - DNA/chemistry
MH  - Epoxy Compounds/*chemical synthesis/chemistry
MH  - Guanine/*analogs & derivatives/chemistry
MH  - Guanosine/chemistry
MH  - Ilizarov Technique
MH  - Magnetic Resonance Spectroscopy
MH  - Mass Spectrometry
MH  - Spectrophotometry, Ultraviolet
EDAT- 1997/07/01 00:00
MHDA- 1997/07/01 00:01
CRDT- 1997/07/01 00:00
PHST- 1997/07/01 00:00 [pubmed]
PHST- 1997/07/01 00:01 [medline]
PHST- 1997/07/01 00:00 [entrez]
AID - tx970004q [pii]
AID - 10.1021/tx970004q [doi]
PST - ppublish
SO  - Chem Res Toxicol. 1997 Jul;10(7):779-85. doi: 10.1021/tx970004q.