Morris C Q, Tucker G T, Crewe H K, Harlow J R, Woods H F, Lennard M S
University Department of Pharmacology and Therapeutics, Royal Hallamshire Hospital, Sheffield, U.K.
Biochem Pharmacol. 1989 Aug 15;38(16):2639-44. doi: 10.1016/0006-2952(89)90549-2.
The imidazole ring is a common structural feature of some xenobiotics that inhibit cytochrome P-450-catalysed reactions. Histamine is a 4-substituted imidazole and a preliminary study has shown it to be an inhibitor of rat liver microsomal drug oxidation. This work has now been extended. Histamine appears to be a competitive inhibitor of the alpha-hydroxylation (HM) (Ki = 164 microM; IC50 at 20 microM = 308 microM) and O-demethylation (ODM) (Ki = 243 microns; IC50 at 20 microM = 400 microM) of metoprolol in rat liver microsomes. Of the metabolites of histamine only N-acetylhistamine showed comparable inhibitory potency to that of the parent compound. Histamine impaired the disappearance of lignocaine when incubated with rat liver microsomes. This was accompanied by a corresponding inhibition of 3-hydroxy-lignocaine appearance. Histamine produced a type II spectral interaction with rat liver microsomes (lambda max = 432 nm, lambda min = 408 nm; Ks = 0.11 mM). When histamine was incubated alone with rat liver microsomes no loss of substrate was observed. The oxidation of metoprolol by human liver microsomes was impaired by histamine (IC50 values for ODM appearance at 25 microM: liver HL1 greater than 10, HL3 = 3.8 and HL4 = 3.7 mM). In comparison, cimetidine had an IC50 value of 1.5 mM using microsomes from liver HL3. Addition of histamine impaired the elimination of metoprolol by the isolated perfused rat liver in a dose-dependent manner (P less than 0.001, one-way analysis of variance). These data demonstrate that histamine can enter hepatocytes, interact with cytochrome P-450 and inhibit some drug oxidation reactions. The physiological relevance of inhibition of drug metabolism by histamine remains to be determined.
咪唑环是一些抑制细胞色素P - 450催化反应的外源性物质的共同结构特征。组胺是一种4 - 取代咪唑，一项初步研究表明它是大鼠肝微粒体药物氧化的抑制剂。这项工作现已得到扩展。组胺似乎是大鼠肝微粒体中美托洛尔α - 羟基化（HM）（Ki = 164微摩尔；20微摩尔时的IC50 = 308微摩尔）和O - 去甲基化（ODM）（Ki = 243微米；20微摩尔时的IC50 = 400微摩尔）的竞争性抑制剂。在组胺的代谢产物中，只有N - 乙酰组胺表现出与母体化合物相当的抑制效力。当与大鼠肝微粒体一起孵育时，组胺会损害利多卡因的消失。这伴随着对3 - 羟基利多卡因出现的相应抑制。组胺与大鼠肝微粒体产生II型光谱相互作用（λmax = 432纳米，λmin = 408纳米；Ks = 0.11毫摩尔）。当组胺单独与大鼠肝微粒体孵育时，未观察到底物损失。组胺会损害人肝微粒体对美托洛尔的氧化（25微摩尔时ODM出现的IC50值：肝HL1大于10，HL3 = 3.8，HL4 = 3.7毫摩尔）。相比之下，使用来自肝HL3的微粒体时，西咪替丁的IC50值为1.5毫摩尔。添加组胺会以剂量依赖的方式损害离体灌注大鼠肝脏对美托洛尔的清除（P < 0.001，单因素方差分析）。这些数据表明组胺可以进入肝细胞，与细胞色素P - 450相互作用并抑制一些药物氧化反应。组胺对药物代谢抑制的生理相关性仍有待确定。
