Yang Richard, Hey John A, Aslanian Robert, Rizzo Charles A
Schering-Plough Research Institute, Allergy, Kenilworth, NJ 07033, USA.
Pharmacology. 2002 Nov;66(3):128-35. doi: 10.1159/000063794.
Optical difference spectroscopy was used to identify and quantify human adrenal microsomal and mitochondrial cytochrome P450 enzyme interactions with the histamine H(3) receptor antagonists thioperamide, clobenpropit and ciproxifan. Addition of these structurally diverse imidazole H(3) receptor antagonists to cytochrome-P450-containing human adrenal microsomal and mitochondrial preparations resulted in concentration-dependent type II optical difference spectra. Respective spectral dissociation constants (K(S)) for the drug interactions with human adrenal microsomal and mitochondrial cytochrome P450 were 1.5 and 1.6 micromol/l for thioperamide, 3.1 and 0.28 micromol/l for clobenpropit and 0.10 and 0.11 micromol/l for ciproxifan. The three compounds demonstrated a similar activity profile in cytochrome-P450-containing bovine adrenal microsomal and mitochondrial preparations. Findings indicate direct coordination of these imidazole-containing H(3) receptor antagonists with the heme moiety of human adrenal cytochrome P450 isozymes.
利用光学差示光谱法来鉴定和定量人肾上腺微粒体及线粒体细胞色素P450酶与组胺H(3)受体拮抗剂硫代哌啶、氯苯丙哌嗪和西普司特之间的相互作用。将这些结构各异的咪唑H(3)受体拮抗剂添加到含细胞色素P450的人肾上腺微粒体及线粒体制剂中，会产生浓度依赖性的II型光学差示光谱。硫代哌啶与人肾上腺微粒体及线粒体细胞色素P450药物相互作用的各自光谱解离常数（K(S)）分别为1.5和1.6微摩尔/升，氯苯丙哌嗪为3.1和0.28微摩尔/升，西普司特为0.10和0.11微摩尔/升。这三种化合物在含细胞色素P450的牛肾上腺微粒体及线粒体制剂中表现出相似的活性特征。研究结果表明，这些含咪唑的H(3)受体拮抗剂与人肾上腺细胞色素P450同工酶的血红素部分直接配位。
