Identification of an inducible form of cytochrome P-450 in human liver.
Identification of an inducible form of cytochrome P-450 in human liver.
复制标题
人肝脏中细胞色素 P-450 诱导形式的鉴定。
DOI：
10.1073/pnas.82.18.6310
复制
发表时间：
1985
影响因子：
11.1
通讯作者：
Guzelian,PS
中科院分区：
文献类型：
--
作者：
Watkins,PB;Wrighton,SA;Maurel,P;Schuetz,EG;Mendez-Picon,G;Parker,GA;Guzelian,PS
目前还没有确定人类肝脏是否含有类似于催化动物体内异物氧化代谢的诱导性细胞色素P-450。我们对从8名患者分离的肝微粒体进行了免疫印迹分析，发现每个微粒体都含有一种被称为HLP的细胞色素P-450，它与针对P-450P的抗体发生反应，P-450P是一种大鼠肝细胞色素，可被抗糖皮质激素孕烯醇酮-16α-碳腈、糖皮质激素、抗癫痫药物和大环内酯类抗生素如三乙酰庆大霉素诱导。在接受地塞米松和抗癫痫药物治疗的两名患者以及接受三乙酰庆大霉素治疗的一名患者中，免疫反应阳性HLP的浓度以及将红霉素去甲基化和/或将三乙酰庆大霉素转化为与细胞色素P-450血红素形成光谱络合物的代谢物的能力(P-450P在大鼠肝脏中所特有的催化特性)与未接受诱导药物的患者相比显著升高。我们对HLP进行了纯化，发现它在兔(LM3c)中与P-450P及其同系物具有免疫化学相关性，在重组系统中活性去甲基化红霉素，表现出与P-450P相同的凝胶迁移率，其NH2末端氨基酸序列与孕烯醇酮-16α-碳腈诱导的大鼠细胞色素P-450有57%的同源性。我们得出结论，HLP是糖皮质激素诱导的细胞色素P-450多基因家族的人类代表。
It has not yet been determined whether human liver contains inducible cytochromes P-450 similar to those that catalyze the oxidative metabolism of foreign substances in animals. We carried out immunoblot analyses of liver microsomes isolated from eight patients and found that each contained a cytochrome P-450, termed HLp, that reacted with antibodies directed against P-450p, a rat liver cytochrome that is inducible by the anti-glucocorticoid pregnenolone-16 alpha-carbonitrile, by glucocorticoids, by anti-seizure drugs, and by such macrolide antibiotics as triacetyloleandomycin. In the two patients who received dexamethasone and anti-seizure medications and in the one patient who was given triacetyloleandomycin, the concentrations of immunoreactive HLp and the ability to demethylate erythromycin and/or to convert triacetyloleandomycin to a metabolite that forms a spectral complex with cytochrome P-450 heme (catalytic properties unique to P-450p in rat liver) were significantly higher as compared to the values for patients who received no inducing drugs. We purified HLp to homogeneity and found that it was immunochemically related to P-450p and to its homologue in the rabbit (LM3c), actively demethylated erythromycin in a reconstituted system, exhibited electrophoretic mobility identical to that of P-450p, and shared 57% homology in its NH2-terminal amino acid sequence with that of a pregnenolone-16 alpha-carbonitrile-inducible rat cytochrome P-450. We conclude that HLp is a human representative of the multigene family of the glucocorticoid-inducible cytochromes P-450.