Document Detail

Structures and biological properties of DNA adducts derived from N-nitroso bile acid conjugates.
MedLine Citation:
PMID:  16533019     Owner:  NLM     Status:  MEDLINE    
A kind of N-nitrosobile acid conjugate, N-nitrosotaurocholic acid (NO-TCA), was incubated with calf thymus DNA, and formation of an adduct was detected by the 32P-postlabeling method under nuclease P1 conditions. To examine the nucleotides containing the adduct from NO-TCA, each of 2'-deoxyribonucleotide 3'-monophosphates (3'-dAp, 3'-dGp, 3'-dCp, or 3'-Tp) was incubated with NO-TCA. The same adduct spot was detected in the reaction of NO-TCA with 3'-dCp. The structure of this adduct was determined to be 3-ethanesulfonic acid-dC by several spectrometry techniques. Moreover, bulky adducts containing bile acid moiety were also produced from the reaction of NO-TCA with 3'-dCp and 3'-dAp. From comparison with spectral data for authentic compounds, these adducts were concluded to be N4-cholyl-dC and N6-cholyl-dA. N4-Cholyl-dC and N6-cholyl-dA were also detected in calf thymus DNA treated with NO-TCA. In addition, 3-ethanesulfonic acid-dC and N4-deoxycholyl-dC were found to be produced from N-nitrosotaurodeoxycholic acid (NO-TDCA) with dC. NO-TCA and NO-TDCA induced mutations in Salmonella typhimurium TA100 but not in TA98. Mutational spectrum analysis revealed that NO-TCA induced G to A transitions predominantly. When NO-TCA (250 mg/kg) was singly administered to male Wistar rats by gavage, both ethanesulfonic acid-dC and N4-cholyl-dC could be detected in the glandular stomach and colon. The levels of ethanesulfonic acid-dC were 0.22-0.29 per 10(6) nucleotides, but values for N4-cholyl-dC were about 500-fold lower. These observations suggest that N-nitroso bile acid conjugates, NO-TCA and NO-TDCA, may induce G to A base substitutions in genes via DNA adduct formation, producing ethanesulfonic acid- and/or (deoxy)cholic acid-DNA and, therefore, may be related to human carcinogenesis as endogenous mutagens.
Yukari Totsuka; Rena Nishigaki; Shigeki Enomoto; Takeji Takamura-Enya; Ken-ichi Masumura; Takehiko Nohmi; Nobuo Kawahara; Takashi Sugimura; Keiji Wakabayashi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Chemical research in toxicology     Volume:  18     ISSN:  0893-228X     ISO Abbreviation:  Chem. Res. Toxicol.     Publication Date:  2005 Oct 
Date Detail:
Created Date:  2006-03-14     Completed Date:  2007-04-24     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8807448     Medline TA:  Chem Res Toxicol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1553-62     Citation Subset:  IM    
Cancer Prevention Basic Research Project, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan.
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MeSH Terms
Alkanesulfonates / chemistry
Bile Acids and Salts / chemistry*,  metabolism
DNA Adducts / chemistry*,  metabolism
Gastrointestinal Tract / metabolism
Mutagens / toxicity
Nitrosamines / chemistry*,  metabolism,  toxicity
Rats, Wistar
Salmonella typhimurium / drug effects,  genetics
Taurodeoxycholic Acid / chemistry,  metabolism
Reg. No./Substance:
0/Alkanesulfonates; 0/Bile Acids and Salts; 0/DNA Adducts; 0/Mutagens; 0/Nitrosamines; 516-50-7/Taurodeoxycholic Acid; 594-45-6/ethane sulfonate; 82660-96-6/N-nitrosotaurocholic acid

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