Alkylation of 2'-Deoxynucleosides and DNA by Quinone Methides Derived from 2,6-Di-tert-butyl-4-methylphenol

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• 作者：Mark A. Lewis ; Darla Graff Yoerg ; Judy L. Bolton ; and John A. Thompson
• 刊名：Chemical Research in Toxicology
• 出版年：1996
• 出版时间：November 1996
• 年：1996
• 卷：9
• 期：8
• 页码：1368 - 1374
• 全文大小：233K
• 年卷期：v.9,no.8(November 1996)
• ISSN：1520-5010

文摘

4-Alkylphenols, such as the antioxidant2,6-di-tert-butyl-4-methylphenol (BHT), exhibittoxicities that appear to be mediated by their oxidative metabolism toelectrophilic quinonemethides. Reactions of these Michael acceptors with simplenucleophiles and proteins havebeen reported, but little information is available on quinone methidebinding to the competingnucleophilic sites in DNA. In the present investigation,2'-deoxynucleoside adducts generatedin vitro with two BHT-derived quinone methides,2,6-di-tert-butyl-4-methylenecyclohexa-2,5-dienone and6-tert-butyl-2-(2'-hydroxy-1',1'-dimethylethyl)-4-methylenecyclohexa-2,5-dienone(BHTOH-QM) were isolated and identified. Both quinone methidesproduced adducts at the1- and N²-positions of deoxyguanosine (dG) and theN⁶-position of deoxyadenosine (dA). Inaddition, a labile adduct formed at the 7-position of dG, whichdegraded to the corresponding7-alkylguanine derivative. Additional work was conducted withBHTOH-QM, the more reactiveof the two quinone methides. This species also formed stableadducts at the N⁴-position ofdeoxycytosine (dC) and the 3-position of thymidine and formed a labileadduct at the 3-positionof dC that underwent hydrolytic cleavage to regenerate dC. Inmixtures of deoxynucleosidestreated with [¹⁴C]BHTOH-QM, alkylation occurredprimarily at the N²- and 7-positions of dGand the N⁶-position of dA and occurred secondarily at the1-position of dG. Treatment of calfthymus DNA with this quinone methide yieldedN⁶-dA and N²-dG adductswith the formerpredominating. The unstable 7-dG adduct was detected by analysisof the 7-alkylguanineproduct from depurination. These results demonstrate that quinonemethides are most likelyto damage DNA through alkylation of the exocyclic amino groups ofpurine residues and possiblyalso by attack at the 7-position of dG followed bydepurination.