MECHANISMS OF REACTION OF BENZO(A)PYRENE-7,8-DIOL-9,10-EPOXIDE WITH DNA IN AQUEOUS-SOLUTIONS
MECHANISMS OF REACTION OF BENZO(A)PYRENE-7,8-DIOL-9,10-EPOXIDE WITH DNA IN AQUEOUS-SOLUTIONS
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DOI：
10.1016/0301-4622(84)80012-5
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发表时间：
1984-01-01
影响因子：
3.8
通讯作者：
HARVEY, RG
中科院分区：
文献类型：
--
作者：
GEACINTOV, NE;HIBSHOOSH, H;HARVEY, RG
研究了[致癌物]代谢物模型化合物苯并(a)芘-7,8-二醇-9,10-环氧化物（BPDE）在水（双链）DNA溶液中的物理和化学反应途径与温度（0℃~ 30℃）的关系。C)、pH（7.0-9.5）、NaCl浓度（0-1.5M）和DNA浓度，阐明该环氧二醇在核酸存在下的多种反应机理之间的关系。反应途径为：与DNA形成非共价插层络合物，以平衡常数K为表征，Xb为物理结合的分子比例；与DNA结合的BPDE加速水解；与DNA的共价结合；水解游离BPDE （kh）。DNA诱导BPDE水解成四醇和与DNA的共价结合是平行的伪一级反应。在BPDE和DNA之间快速（ms时间尺度）形成非共价复合物之后，一个慢得多的(.apprx。H+依赖（特定或一般酸催化）形成dna结合的三醇羰基离子（速率常数k3）发生。pH 7.0时k3的活化能为8.7 +-。0.9 kcal/mol，低于缓冲溶液中游离BPDE的水解活化能(14.2 .+-。0.7 kcal/mol)，这部分解释了BPDE与DNA络合后加速水解的原因。三醇羰基离子形成后，与水迅速反应生成四醇（速率常数kT），或与DNA共价结合（速率常数kc）。BPDE分子中发生共价结合的部分是fcov .apprxeq。kc/(kc + kT) = 0.10，与BPDE总反应速率常数k = kh(1-Xb)+k3Xb无关。1.0，或独立于Xb，只要k3Xb .mchgt。kh (1-Xb)。在Xb = 0.9时，fcov与pH（7.0-9.5）无关，尽管k在该pH范围内表现出70倍的变化。（k3 = kh）。同样，fcov与温度无关（0度-30度）。C)，而k的变化因子约为。3. 在0 ~ 1.5 M NaCl范围内，fcov从0.10 ~ 0.04降低。这些变化归因于盐引起的因子k3、Xb和kc/kT比值的变化。
The physical and chemical reaction pathways of the [carcinogen] metabolite model compound benzo(a)pyrene-7,8-diol-9,10-epoxide (BPDE) in aqueous (double-stranded) DNA solutions was investigated as a function of temperature (0.degree.-30.degree. C), pH (7.0-9.5), NaCl concentration (0-1.5M) and DNA concentration to clarify the relationships between the multiple reaction mechanisms of this diol epoxide in the presence of nucleic acids. The reaction pathways are: noncovalent intercalative complex formation with DNA, characterized by the equilibrium constant K, and Xb the fraction of molecules physically bound; accelerated hydrolysis of BPDE bound to DNA; covalent binding to DNA; and hydrolysis of free BPDE (kh). The DNA-induced hydrolysis of BPDE to tetraols and the covalent binding to DNA are parallel pseudeo-1st-order reactions. Following the rapid (ms time scale) noncovalent complex formation between BPDE and DNA, a much slower (.apprx. min) H+-dependent (either specific or general acid catalysis ) formation of a DNA-bound triol carbonium ion (rate constant k3) occurs. At pH 7.0 the activation energy of k3 is 8.7 .+-. 0.9 kcal/mol, which is lower than the activation energy of hydrolysis of free BPDE in buffer solution (14.2 .+-. 0.7 kcal/mol), and which thus partially accounts for the acceleration of hydrolysis of BPDE upon complexation with DNA. The formation of the triol carbonium ion is followed by a rapid reaction with either water to form tetraols (rate constant kT), or covalent bindings to DNA (kc). The fraction of BPDE molecules which undergo covalent binding is fcov .apprxeq. kc/(kc + kT) = 0.10 and is independent of the overall BPDE reaction rate constant k = kh(1-Xb)+k3Xb if Xb .fwdarw. 1.0, or is independent of Xb as long as k3Xb .mchgt. kh(1-Xb). At Xb = 0.9, fcov is independent of pH (7.0-9.5) even though k exhibits a 70-fold variation in this pH range and k .fwdarw. kh above pH 9 (k3 = kh). Similarly, fcov is independent of temperature (0.degree.-30.degree. C), while k varies by a factor of .apprx. 3. In the range of 0-1.5 M NaCl, fcov decreases from 0.10-0.04. These variations are attributed to a combination of salt-induced variations in the factors k3, Xb and the ratio kc/kT.