THE INFLUENCE OF THE P-ALKYL SUBSTITUENT ON THE ISOMERIZATION OF O-QUINONES TO P-QUINONE METHIDES - POTENTIAL BIOACTIVATION MECHANISM FOR CATECHOLS
THE INFLUENCE OF THE P-ALKYL SUBSTITUENT ON THE ISOMERIZATION OF O-QUINONES TO P-QUINONE METHIDES - POTENTIAL BIOACTIVATION MECHANISM FOR CATECHOLS
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DOI：
10.1021/tx00046a007
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发表时间：
1995-06-01
影响因子：
4.1
通讯作者：
BOLTON, JL
中科院分区：
文献类型：
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作者：
IVERSON, SL;HU, LQ;BOLTON, JL
以前，我们已经证明了肝癌致癌物黄樟素(1-烯丙基-3，4-(亚甲二氧基)苯)存在一个额外的生物激活途径，该途径可能有助于其毒性效应：亚甲二氧基环的初始O-脱烷基，形成邻苯二酚，羟基茶酚(HC，1-烯丙基-3，4-二羟基苯)，2电子氧化成邻苯二酚(4-烯丙基-3，5-环己二烯-1，2-二酮)，以及异构化，形成更亲电的对苯二酮甲基(2-hydroxy-4-allylidene-2，5-cyclohexadien-1-one)[Bolton，J.L.，Acay，N.M.，and Vukomanovic，V.(1994)化学。Toxicol资源。7,443-450]。在本研究中，我们探索了改变4-位上的pi-共轭，以及由4-丙基儿茶酚(1)、2，3-二羟基-5，6，7，8-四氢萘酚(2)和4-肉桂基邻苯二酚(3)形成的奎诺酮类化合物的反应活性和初始形成的邻苯二酮对QMS异构化的影响。我们选择性地将儿茶酚氧化成相应的邻苯二酚或对苯二酚甲基，并用谷胱甘肽(GSH)捕获这些反应性亲电分子。GSH加合物的结构经紫外光谱、核磁共振和质谱学确证。在谷胱甘肽存在的情况下，微体与亲代儿茶酚孵育只产生邻苯二酮型谷胱甘肽结合物。然而，如果在初始孵育时间后加入捕捉剂(GSH)，则可以同时观察到邻苯二酚和对苯二酚甲基GSH偶联物。结果表明，邻苯二酚在对位延伸的pi-共轭反应提高了邻苯二酚异构化为甲基苯二酚的速率。因此，邻苯二酚的半衰期按如下顺序递减：1>；2>；HC>；3。为了支持这一点，AMI半经验计算也显示出相同的趋势：随着4-位pi-共轭的延长，邻苯二酚甲醚的稳定性增加。最后，动力学研究表明，随着pi-共轭程度的降低，对苯二酚与水的反应活性增加。这些数据提供了进一步的证据，表明邻苯二酚形成亲电性的甲基对苯二酚可能是合成和自然产生的4-烷基儿茶酚的一般生物活化途径。
Previously, we have shown that an additional bioactivation pathway for the hepatocarcinogen safrole (1-allyl-3,4-(methylenedioxy)benzene) exists which may contribute to its toxic effects: initial O-dealkylation of the methylenedioxy ring, forming the catechol, hydroxychavicol (HC, 1-allyl-3,4-dihydroxybenzene), 2-electron oxidation to the o-quinone (4-allyl-3,5-cyclohexadien-1,2-dione), and isomerization, forming the more electrophilic p-quinone methide (2-hydroxy-4-allylidene-2,5-cyclohexadien-1-one) [Bolton, J. L., Acay, N. M., and Vukomanovic, V. (1994) Chem. Res. Toxicol. 7, 443-450]. In the present investigation, we explored the effects of changing pi-conjugation at the 4-position an both the rate of isomerization of the initially formed o-quinones to the QMs and the reactivity of the quinoids formed from 4-propylcatechol (1), 2,3-dihydroxy-5,6,7,8-tetrahydronaphthal (2), and 4-cinnamylcatechol (3). We selectively oxidized the catechols to the corresponding o-quinones or p-quinone methides and trapped these reactive electrophiles with glutathione (GSH). The GSH adducts were fully characterized by UV, NMR, and mass spectrometry. Microsomal incubations with the parent catechols in the presence of glutathione produced only o-quinone glutathione conjugates. However, if the trapping agent (GSH) was added after an initial incubation time, both o-quinone and p-quinone methide GSH conjugates were observed. The results indicate that extended pi-conjugation at the para position enhances the rate of isomerization of the o-quinone to the quinone methide. Thus the half-life of the o-quinones decreased in the following order: the o-quinone of 1 > 2 > HC > 3. In support of this, AMI semiempirical calculations also showed the same trend: an increase in stability of the quinone methide relative to the o-quinone with extending pi-conjugation at the 4-position. Finally, kinetic studies showed that the reactivity of the quinone methides with water increases with decreasing pi-conjugation. These data provide further evidence that formation of these electrophilic quinone methides from o-quinones may be a general bioactivation pathway for synthetic and naturally occurring 4-alkylcatechols.