Abstract

Over 3 billion kg/yr of vinyl chloride (VC) are produced in the U.S. VC has been amply documented as a human carcinogen associated with liver haemoangiosarcoma and tumors of the brain and lungs. No mechanism for its tumorigenicity has emerged, even though tumors are easily induced in rodents, and VC and its mutagenic metabolites, chloroethylene oxide (CEO) and chloroacetaldehyde (CAA) have been intensively studied. The known in vivo products of VC are three cyclic etheno bases, apparently derived from CAA; 7-(2-oxoethyl)G is apparently derived from CEO. Our long-term objective is to understand the molecular mechanism of initiation by VC, related carcinogens and their common metabolites. This approach has three specific aims: (1) To use physical, chemical, and biochemical methods to study three known etheno products (l,N6-etheno A, 3, N4-etheno C, and N2,3-etheno G) of VC- nucleic acid reaction in terms of effect on polymer structure, replication and fidelity. Special emphasis will be placed on N2,3- etheno G which can form two hydrogen bonds with C or T. (2) To investigate the formation of additional derivatives by epoxides and aldehydes, including several biologically important simple mono- and bifunctional agents (e.g., ethylene oxide, cyanoethylene oxide, chloroacetaldehyde). (3) To study the initial chemical steps in formation of cyclic derivatives and crosslinks by the aldehyde and halide functions of the VC metabolites. Our purpose is to search for biologically significant chemical events that could be mutagenic or lethal. The methods and approaches will utilize chemical synthesis of modified dNTPs, rNTPs, with and without radiolabel; kinetics and sequence of aldehyde/epoxide reactions; helix-coil transitions of polymers and oligomers containing modified etheno derivatives; optical methods (UV, IR, fluorescence); HPLC, gel electrophoresis, nucleotide sequencing; in vitro replication of defined oligomers; and utilization of etheno NTPs in site-directed mutagenesis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA047723-05
Application #
3191485
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1988-02-15
Project End
1994-01-31
Budget Start
1992-02-01
Budget End
1994-01-31
Support Year
5
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Lawrence Berkeley National Laboratory
Department
Type
Organized Research Units
DUNS #
078576738
City
Berkeley
State
CA
Country
United States
Zip Code
94720

  Publications

Xie, Zhongwen; Zhang, Yangbin; Guliaev, Anton B et al. (2005) The p-benzoquinone DNA adducts derived from benzene are highly mutagenic. DNA Repair (Amst) 4:1399-409
Guliaev, Anton B; Singer, B; Hang, Bo (2004) Chloroethylnitrosourea-derived ethano cytosine and adenine adducts are substrates for Escherichia coli glycosylases excising analogous etheno adducts. DNA Repair (Amst) 3:1311-21
Guliaev, Anton B; Hang, Bo; Singer, B (2004) Structural insights by molecular dynamics simulations into specificity of the major human AP endonuclease toward the benzene-derived DNA adduct, pBQ-C. Nucleic Acids Res 32:2844-52
Hang, Bo; Singer, B (2003) Protein-protein interactions involving DNA glycosylases. Chem Res Toxicol 16:1181-95
Hang, Bo; Chenna, Ahmed; Guliaev, Anton B et al. (2003) Miscoding properties of 1,N6-ethanoadenine, a DNA adduct derived from reaction with the antitumor agent 1,3-bis(2-chloroethyl)-1-nitrosourea. Mutat Res 531:191-203
Singer, B; Medina, Michael; Zhang, Yanbin et al. (2002) 8-(Hydroxymethyl)-3,N(4)-etheno-C, a potential carcinogenic glycidaldehyde product, miscodes in vitro using mammalian DNA polymerases. Biochemistry 41:1778-85
Hang, Bo; Downing, Gary; Guliaev, Anton B et al. (2002) Novel activity of Escherichia coli mismatch uracil-DNA glycosylase (Mug) excising 8-(hydroxymethyl)-3,N4-ethenocytosine, a potential product resulting from glycidaldehyde reaction. Biochemistry 41:2158-65
Guliaev, Anton B; Hang, Bo; Singer, B (2002) Structural insights by molecular dynamics simulations into differential repair efficiency for ethano-A versus etheno-A adducts by the human alkylpurine-DNA N-glycosylase. Nucleic Acids Res 30:3778-87
Sagi, J; Guliaev, A B; Singer, B (2001) 15-mer DNA duplexes containing an abasic site are thermodynamically more stable with adjacent purines than with pyrimidines. Biochemistry 40:3859-68
Sagi, J; Perry, A; Hang, B et al. (2000) Differential destabilization of the DNA oligonucleotide double helix by a T.G mismatch, 3,N(4)-ethenocytosine, 3,N(4)-ethanocytosine, or an 8-(hydroxymethyl)-3,N(4)-ethenocytosine adduct incorporated into the same sequence contexts. Chem Res Toxicol 13:839-45

Showing the most recent 10 out of 44 publications