LaBella F S, Queen G
Department of Pharmacology and Therapeutics, University of Manitoba, Faculty of Medicine, Winnipeg, Canada.
Eur J Pharmacol. 1995 Oct 6;293(3):231-5. doi: 10.1016/0926-6917(95)00022-4.
We reported previously that 18 compounds varying in general anesthetic potency by up to 66 000-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 isoenzymes may contribute to pharmacological effects of the anesthetics associated with levels of drug well below concentrations that effect general anesthesia.
我们之前报道过，18种化合物的全身麻醉效力相差高达66000倍，在麻醉浓度下，它们会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比林的代谢。现在，我们报道P450介导的苯胺对羟基化作用对麻醉剂更为敏感。7种化合物的酶抑制Ki值与其各自的麻醉效力相近，另外7种化合物的Ki值比各自的麻醉效力低5至40倍。与P450具有类似苯胺结合模式的内源性底物包括组胺及相关咪唑。丙酮以及卤代化合物氟烷、恩氟烷和氯仿，在远低于和高于其EC50值的浓度下均能刺激苯胺羟化酶活性。这些对通用P450同工酶的强效作用可能有助于麻醉剂在远低于产生全身麻醉浓度的药物水平时产生药理作用。
