Subanesthetic concentrations of drugs inhibit cytochrome P450-mediated metabolism of aniline

Frank S. LaBella, Gary Queen
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引用次数: 6

Abstract

We reported previously that 18 compounds varying in general anesthetic potency by up to 66000-fold inhibited, at anesthetic concentrations, the metabolism of arachidonic acid and aminopyrine by cytochrome P450 monooxygenases in rat liver microsomes. Now, we report that P450-mediated para-hydroxylation of aniline is more sensitive to the anesthetics. The Ki values for enzyme inhibition for seven compounds were close to and for seven compounds 5–40 times less than their respective anesthetic potencies. Endogenous substrates with an aniline-like binding mode to P450 include histamine and related imidazoles. Acetone and each of the halogenated compounds, halothane, enflurane, and chloroform, stimulated aniline hydroxylase activity at concentrations well below and above their EC50 values. These potent actions on the universal P450 isozymes may contribute to pharmacological effects of the anesthetics associated with levels of drug well below concentrations that effect general anesthesia.

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亚麻醉浓度的药物抑制细胞色素p450介导的苯胺代谢
我们之前报道了18种全麻效力变化高达66,000倍的化合物在麻醉浓度下抑制大鼠肝微粒体中细胞色素P450单加氧酶对花生四烯酸和氨基吡啶的代谢。现在,我们报道p450介导的苯胺对羟基化反应对麻醉剂更敏感。7种化合物的酶抑制Ki值接近于其麻醉效力,7种化合物的Ki值小于其麻醉效力的5-40倍。与P450具有类似苯胺结合模式的内源性底物包括组胺和相关咪唑。丙酮和每一种卤化化合物,氟烷、安氟醚和氯仿,在远低于或高于其EC50值的浓度下刺激苯胺羟化酶的活性。这些对通用P450同工酶的有效作用可能有助于麻醉药的药理作用,其药物水平远低于影响全身麻醉的浓度。
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