Melikian A A, Leszczynska J M, Amin S, Hecht S S, Hoffmann D, Pataki J, Harvey R G
Cancer Res. 1985 May;45(5):1990-6.
The rates of hydrolysis in the absence and presence of native and denatured DNA, and the extents of DNA binding of five dihydrodiol epoxides derived from 5-methylchrysene (5-MeC) and chrysene have been determined. The compounds studied were: trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC; trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydro-5-Mec; trans-1,2-dihydroxy-syn-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC; trans-7,8-dihydroxy-syn-9,10-epoxy-7,8,9,10-tetrahydro-5-MeC; and trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydrochrysene. In the absence of DNA, at pH 7 and 37 degrees C half-lives of trans-1,2-dihydroxy-syn-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC and trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC were similar, t 1/2 = 62 and 59 min, while trans-7,8-dihydroxy-syn-9,10-epoxy-7,8,9,10-tetrahydro-5-MeC hydrolyzed faster than trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydro-5-MeC, t 1/2 = 5.4 versus 17.5 min; trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydrochrysene had the slowest rate of hydrolysis, t 1/2 = 104 min. Studies of the effects of native and denatured DNA on the rates of hydrolysis of the dihydrodiol epoxides indicated that native DNA remarkably accelerated these rates for all dihydrodiol epoxides, but the degree of acceleration varied for the different dihydrodiol epoxides. The acceleration of hydrolytic rates by native DNA relative to that by denatured DNA was correlated with the covalent binding of these dihydrodiol epoxides with DNA in vitro. The catalytic effect of DNA in enhancing the rates of hydrolysis of dihydrodiol epoxides and the relative extents of covalent binding of the dihydrodiol epoxides to DNA were in the following order: trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC greater than trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydro-5-MeC greater than trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydrochrysene greater than trans-1,2-dihydroxy-syn-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC greater than trans-7,8-dihydroxy-syn-9,10-epoxy-7,8,9,10-tetrahydro-5-MeC. The results of this study suggest that physical interactions with DNA are important in determining the relative extents of binding of these dihydrodiol epoxides to DNA in vitro.
已测定了5-甲基屈（5-MeC）和屈衍生的5种二氢二醇环氧化物在不存在和存在天然及变性DNA情况下的水解速率，以及它们与DNA的结合程度。所研究的化合物为：反式-1,2-二羟基-反式-3,4-环氧-1,2,3,4-四氢-5-MeC；反式-7,8-二羟基-反式-9,10-环氧-7,8,9,10-四氢-5-MeC；反式-1,2-二羟基-顺式-3,4-环氧-1,2,3,4-四氢-5-MeC；反式-7,8-二羟基-顺式-9,10-环氧-7,8,9,10-四氢-5-MeC；以及反式-1,2-二羟基-反式-3,4-环氧-1,2,3,4-四氢屈。在不存在DNA的情况下，于pH 7和37℃时，反式-1,2-二羟基-顺式-3,4-环氧-1,2,3,4-四氢-5-MeC和反式-1,2-二羟基-反式-3,4-环氧-1,2,3,4-四氢-5-MeC的半衰期相似，t1/2分别为62分钟和59分钟，而反式-7,8-二羟基-顺式-9,10-环氧-7,8,9,10-四氢-5-MeC的水解速度比反式-7,8-二羟基-反式-9,10-环氧-7,8,9,10-四氢-5-MeC快，t1/2分别为5.4分钟和17.5分钟；反式-1,2-二羟基-反式-3,4-环氧-1,2,3,4-四氢屈的水解速率最慢，t1/2为104分钟。对天然及变性DNA对二氢二醇环氧化物水解速率影响的研究表明，天然DNA显著加快了所有二氢二醇环氧化物的水解速率，但不同二氢二醇环氧化物的加速程度有所不同。相对于变性DNA而言，天然DNA对水解速率的加速作用与这些二氢二醇环氧化物在体外与DNA的共价结合相关。DNA增强二氢二醇环氧化物水解速率的催化作用以及二氢二醇环氧化物与DNA共价结合的相对程度顺序如下：反式-1,2-二羟基-反式-3,4-环氧-1,
