Structures and Biological Properties of DNA Adducts Derived from N-Nitroso Bile Acid Conjugates

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• 作者：Yukari Totsuka ; Rena Nishigaki ; Shigeki Enomoto ; Takeji Takamura-Enya ; Ken-ichi Masumura ; Takehiko Nohmi ; Nobuo Kawahara ; Takashi Sugimura ; and Keiji Wakabayashi
• 刊名：Chemical Research in Toxicology
• 出版年：2005
• 出版时间：October 2005
• 年：2005
• 卷：18
• 期：10
• 页码：1553 - 1562
• 全文大小：237K
• 年卷期：v.18,no.10(October 2005)
• ISSN：1520-5010

文摘

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-postlabelingmethod under nuclease P1 conditions. To examine the nucleotides containing the adduct fromNO-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-TCAwith 3'-dCp. The structure of this adduct was determined to be 3-ethanesulfonic acid-dC byseveral spectrometry techniques. Moreover, bulky adducts containing bile acid moiety werealso produced from the reaction of NO-TCA with 3'-dCp and 3'-dAp. From comparison withspectral data for authentic compounds, these adducts were concluded to be N⁴-cholyl-dC andN⁶-cholyl-dA. N⁴-Cholyl-dC and N⁶-cholyl-dA were also detected in calf thymus DNA treatedwith NO-TCA. In addition, 3-ethanesulfonic acid-dC and N⁴-deoxycholyl-dC were found to beproduced from N-nitrosotaurodeoxycholic acid (NO-TDCA) with dC. NO-TCA and NO-TDCAinduced mutations in Salmonella typhimurium TA100 but not in TA98. Mutational spectrumanalysis 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 ofethanesulfonic acid-dC were 0.22-0.29 per 10⁶ nucleotides, but values for N⁴-cholyl-dC wereabout 500-fold lower. These observations suggest that N-nitroso bile acid conjugates, NO-TCAand 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 relatedto human carcinogenesis as endogenous mutagens.