Inhibition of trans-dihydrodiol oxidation by the non-steroidal anti-inflammatory drugs.
Inhibition of trans-dihydrodiol oxidation by the non-steroidal anti-inflammatory drugs.
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非甾体抗炎药抑制反式二氢二醇氧化。
DOI：
10.1093/carcin/7.4.583
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发表时间：
1986
期刊：
影响因子：
4.7
通讯作者：
Penning,TM
中科院分区：
文献类型：
--
作者：
Smithgall,TE;Penning,TM
大鼠肝胞质溶胶的均质二氢二醇脱氢酶（EC 1.3.1.20）在艾姆斯试验中降低苯并[a]-芘的致突变性，表明该酶可使该化合物形成的反式二氢二醇类致癌物解毒。本研究首次直接证明了纯化的脱氢酶在生理pH条件下催化强致癌物[1，3- 3 H]（±）-trans-7，8-dihydroxy-7，8-dihydrobenzo-[ajpyrene]的NADP依赖性氧化反应，在底物浓度为20 μM时，氧化反应的初速度为1.8 nmol [3 H]trans-dibydrodiol/min/mg蛋白质。这种潜在的解毒反应被非甾体抗炎药吲哚美辛有效抑制，产生的IC 50值为10 μM。在较高的药物浓度（30 /M）下，抑制持续数小时。在本工作的基础上，合成了苯二氢二醇（反式-1，2-二羟基-3，5-环己二烯）和萘二氢二醇（反式-1，2-二羟基-1，2-二氢萘），作为稀有致癌物反式-7，8-二羟基-7，8-二氢苯并[a]芘的模型化合物，并作为底物进行了研究。苯二氢二醇的Km为1.74 mM，Vmax为530 nmol底物氧化/min/mg蛋白质，而萘二氢二醇的Km为10.71 mM，Vmax为268 nmol氧化/min/mg蛋白质;前一种化合物被氧化为邻苯二酚。八种不同的非甾体抗炎药被发现抑制这些modeltrans-dihydrodiol的氧化，产生的IC 50值相当于或低于峰值血浆浓度观察man. These结果表明，治疗相关浓度的非甾体抗炎药可能会抑制氧化oftrans-dihydrodiol接近致癌物通过这条路线。
The homogeneous dihydrodiol dehydrogenase of rat liver cytosol (EC 1.3.1.20) reduces the mutagenicity of benzo[a]-pyrene in the Ames test, suggesting that the enzyme may detoxify thetrans-dihydrodiol proximate carcinogens formed from this compound. This report directly demonstrates for the first time that the purified dehydrogenase catalyzes the NADP-dependent oxidation of the potent proximate carcinogen [l, 3–3H](±)-trans-7, 8-dihydroxy-7, 8-dihydrobenzo-[ajpyrene at physiological pH. An initial velocity of 1.8 nmol [3H]trans-dibydrodiol oxidized/min/mg protein was observed at a substrate concentration of 20 μM. This potential detoxification reaction was potently inhibited by the non-steroidal anti-inflammatory drug indomethacin, yielding an IC50 value of 10 μM. At higher drug concentrations (30 /M), the inhibition persisted for many hours. In an extension of this work, benzenedihydrodiol (trans-l, 2-dihydroxy-3, 5-cyclo-bexadiene) and naphthalenedihydrodiol (trans-l,2-dihydroxy-1, 2-dihydronaphthalene) were synthesized as models of the scarce proximate carcinogentrans-7, 8-dihydroxy-7, 8-dihydro-benzo[a]pyrene and examined as substrates. The Kmfor ben-zenedihydrodiol was 1.74 mM and the Vmaxwas 530 nmol substrate oxidized/min/mg protein, while the Kmfor naphthalenedihydrodiol was 10.71 mM and the Vmaxwas 268 nmol oxidized/min/mg protein; the former compound was oxidized to catechol. Eight different non-steroidal anti-inflammatory drugs were found to inhibit the oxidation of these modeltrans-dihydrodiols, yielding IC50 values comparable to or lower than peak plasma concentrations observed in man. These results suggest that therapeutically relevant concentrations of the non-steroidal anti-inflammatory drugs may inhibit the oxidation oftrans-dihydrodiol proximate carcinogens by this route.