The primary goal has been the elucidation of the structures of reactive metabolites which are responsible for the carcinogenic, cytotoxic and mutagenic activity of polycyclic aromatic hydrocarbons. The approach taken consists of: i) synthesis of primary and secondary oxidative metabolites, ii) study of the metabolism of the hydrocarbons with liver microsomes, as well as with purified and reconstituted cytochrome P-450 systems with and without epoxide hydrolase, iii) tests for mutagenicity of the synthetic metabolites, iv) elucidation of the roles of the cytochrome P-450 system and epoxide hydrolase in potentiating or obliterating the mutagenicity of these metabolites, v) determination of the carcinogenic activity of these compounds, vi) determination of the reaction rates and nature of the products formed by arene oxides and diol epoxides upon reaction with biopolymers and model compounds, and vii) search for agents capable of preventing the tumorigenic action of active metabolites. Current chemical studies have included a new synthesis of oxepins which form during the preparation of benzo-ring arene oxides from dibromoacetate precursors. In selected cases, predictable from PMO calculations, the arene oxides undergo facile photorearrangements to the same oxepins. Studies of the pH dependent solvolysis of precocene I 3,4-oxide have established an unprecedented change in rate determining step from formation of a carbocation intermediate (low pH) to capture of the carbocation by solvent (high pH). Examination of the nucleotide - catalyzed hydrolysis of benzo(a)pyrene 7,8-diol 9,10-epoxide established the importance of stacking interactions between the nucleotide and the hydrocarbon in this general-acid (phosphate) catalyzed process. Stereoselective metabolism of triphenylene to triphenylene 1,2- oxide enantiomers was shown to be dependent on the cytochrome P- 450 preparation utilized. Tumor studies established that introduction of a 6-fluoro substituent into the highly tumorigenic benzo(a)pyrene 7,8-diol 9,10-epoxide eliminates carcinogenic activity, possibly due to a conformational change.

Project Start
Project End
Budget Start
Budget End
Support Year
21
Fiscal Year
1988
Total Cost
Indirect Cost
Name
U.S. National Inst Diabetes/Digst/Kidney
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Yagi, Haruhiko; Frank, Heinrich; Seidel, Albrecht et al. (2007) Synthesis and absolute configuration of cis- and trans-opened cyclopenta[cd]pyrene 3,4-oxide N2-deoxyguanosine adducts: conversion to phosphoramidites for oligonucleotide synthesis. Chem Res Toxicol 20:650-61
Iyer, Prema C; Yagi, Haruhiko; Sayer, Jane M et al. (2007) 3'-H-phosphonate synthesis of chiral benzo[a]pyrene diol epoxide adducts at N(2) of deoxyguanosine in oligonucleotides. Chem Res Toxicol 20:311-5
Yagi, Haruhiko; Jerina, Donald M (2007) Fluorinated alcohol mediated control over cis vs trans opening of benzo[a]pyrene-7,8-diol 9,10-epoxides at C-10 by the exocyclic amino groups of O6-allyl protected deoxyguanosine and of deoxyadenosine. J Org Chem 72:6037-45
Bauer, Jacob; Xing, Guangxin; Yagi, Haruhiko et al. (2007) A structural gap in Dpo4 supports mutagenic bypass of a major benzo[a]pyrene dG adduct in DNA through template misalignment. Proc Natl Acad Sci U S A 104:14905-10
Wang, Ben; Sayer, Jane M; Yagi, Haruhiko et al. (2006) Facile interstrand migration of the hydrocarbon moiety of a dibenzo[a,l]pyrene 11,12-diol 13,14-epoxide adduct at N2 of deoxyguanosine in a duplex oligonucleotide. J Am Chem Soc 128:10079-84
Johnson, Allison A; Sayer, Jane M; Yagi, Haruhiko et al. (2006) Effect of DNA modifications on DNA processing by HIV-1 integrase and inhibitor binding: role of DNA backbone flexibility and an open catalytic site. J Biol Chem 281:32428-38
Yakovleva, Lyudmila; Handy, Christopher J; Yagi, Haruhiko et al. (2006) Intercalating polycyclic aromatic hydrocarbon-DNA adducts poison DNA religation by Vaccinia topoisomerase and act as roadblocks to digestion by exonuclease III. Biochemistry 45:7644-53
Batra, Vinod K; Shock, David D; Prasad, Rajendra et al. (2006) Structure of DNA polymerase beta with a benzo[c]phenanthrene diol epoxide-adducted template exhibits mutagenic features. Proc Natl Acad Sci U S A 103:17231-6
Choudhary, Saba; Doherty, Kevin M; Handy, Christopher J et al. (2006) Inhibition of Werner syndrome helicase activity by benzo[a]pyrene diol epoxide adducts can be overcome by replication protein A. J Biol Chem 281:6000-9
Chiapperino, Dominic; Cai, Mangmang; Sayer, Jane M et al. (2005) Error-prone translesion synthesis by human DNA polymerase eta on DNA-containing deoxyadenosine adducts of 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene. J Biol Chem 280:39684-92

Showing the most recent 10 out of 64 publications