Vepachedu S R, Ya N, Yagi H, Sayer J M, Jerina D M
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, The National Institutes of Health, Bethesda, Maryland 20892-0820, USA.
Chem Res Toxicol. 2000 Sep;13(9):883-90. doi: 10.1021/tx000073w.
Distributions of adducts formed from each of the four optically active isomers of 3,4-dihydroxy-1,2-epoxy-1,2,3, 4-tetrahydrobenzo[c]phenanthrene and of 7,8-dihydroxy-9,10-epoxy-7,8, 9,10- tetrahydrobenzo[a]pyrene (BcPh and BaP diol epoxides) on reaction with an equimolar mixture of deoxyadenosine and deoxyguanosine 5'-monophosphates were compared with the known adduct distributions from these diol epoxides (DEs) upon reaction with calf thymus DNA in vitro. In the presence of an equimolar (100 mM total) mixture of dAMP and dGMP, the efficiency of formation of all types of adducts relative to tetraols is comparable for both the BaP ( approximately 40-60%) and BcPh ( approximately 30-40%) diol epoxides. This is in contrast to the partitioning between tetraols and adducts observed with DNA, where the BcPh DEs form adducts much more efficiently than the BaP DEs. Preference for trans versus cis ring opening by the exocyclic amino groups of the free nucleotides in the dAMP/dGMP mixture is greater for the DE diastereomer in which the benzylic hydroxyl group and the epoxide oxygen are trans (DE-2). This is qualitatively similar to the preferences for trans versus cis adduct formation on reaction of these isomers with DNA, as well as trans versus cis tetraol formation on their acid hydrolysis. For the BcPh DE isomers, competitive reaction between dGMP and dAMP gives 40-62% of the total exocyclic amino group adducts as dA adducts. A similar distribution of dG versus dA adducts had previously been observed on reaction of the BcPh DEs with DNA, except in the case of (+)-3(R),4(S)-dihydroxy-1(R),2(S)-epoxy-1,2,3, 4-tetrahydrobenzo[c]phenanthrene, which gives approximately 85% dA adducts on reaction with DNA. With the BaP DEs, 60-77% of the exocyclic amino group adducts formed upon competitive reaction with the free nucleotides are derived from dGMP. The observed dG selectivity of these BaP DEs is much smaller with the nucleotide mixture than it is with DNA, leading to the conclusion that DNA structure has a much larger modifying effect on the base selectivity of the BaP relative to the BcPh DEs.
将3,4 - 二羟基 - 1,2 - 环氧 - 1,2,3,4 - 四氢苯并[c]菲和7,8 - 二羟基 - 9,10 - 环氧 - 7,8,9,10 - 四氢苯并[a]芘（苯并[c]菲二醇环氧化物和苯并[a]芘二醇环氧化物，即BcPh和BaP二醇环氧化物）的四种旋光异构体分别与脱氧腺苷和脱氧鸟苷5'-单磷酸的等摩尔混合物反应形成的加合物分布，与这些二醇环氧化物（DEs）在体外与小牛胸腺DNA反应时已知的加合物分布进行了比较。在dAMP和dGMP的等摩尔（总浓度100 mM）混合物存在下，相对于四醇而言，BaP（约40 - 60%）和BcPh（约30 - 40%）二醇环氧化物形成所有类型加合物的效率相当。这与在DNA中观察到的四醇与加合物之间的分配情况形成对比，在DNA中，BcPh DEs形成加合物的效率比BaP DEs高得多。在dAMP/dGMP混合物中，游离核苷酸的环外氨基对反式与顺式开环的偏好对于苄基羟基和环氧基氧为反式的DE非对映异构体（DE - 2）更大。这在定性上类似于这些异构体与DNA反应时对反式与顺式加合物形成的偏好，以及它们酸水解时对反式与顺式四醇形成的偏好。对于BcPh DE异构体，dGMP和dAMP之间的竞争反应产生的环外氨基加合物总量中，40 - 62%为dA加合物。之前在BcPh DEs与DNA反应时也观察到了类似的dG与dA加合物分布，除了(+)-3(R),4(S)-二羟基 - 1(R),2(S)-环氧 - 1,2,3,4 - 四氢苯并[c]菲的情况，它与DNA反应时产生约85%的dA加合物。对于BaP DEs，与游离核苷酸竞争反应形成的环外氨基加合物中，60 - 77%来自dGMP。在核苷酸混合物中观察到的这些BaP DEs的dG选择性比与DNA反应时小得多，由此得出结论，相对于BcPh DEs，DNA结构对BaP的碱基选择性具有更大的修饰作用。
