FORMATION OF AN INACTIVE CYTOCHROME-P-450 FE(II)-METABOLITE COMPLEX AFTER ADMINISTRATION OF TROLEANDOMYCIN IN HUMANS
FORMATION OF AN INACTIVE CYTOCHROME-P-450 FE(II)-METABOLITE COMPLEX AFTER ADMINISTRATION OF TROLEANDOMYCIN IN HUMANS
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DOI：
10.1016/0006-2952(82)90671-2
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发表时间：
1982-01-01
影响因子：
5.8
通讯作者：
BENHAMOU, JP
中科院分区：
文献类型：
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作者：
PESSAYRE, D;LARREY, D;BENHAMOU, JP
醋竹桃霉素[一种大环内酯类抗生素]在大鼠体内诱导自身转化为代谢产物，与还原型细胞色素P-450形成非活性复合物。为了确定在人类中是否发生类似的作用，研究了6名未经治疗的患者和6名用三乙酰竹桃霉素治疗的患者的肝微粒体，每天口服2 g，持续7天。在接受治疗的患者中，NADPH-细胞色素c还原酶活性增加了48%;总细胞色素P-450浓度也增加了，但总细胞色素P-450的33%被三乙酰竹桃霉素代谢物络合。细胞色素P-450 Fe（II）-代谢物复合物表现出相同的性质，在大鼠中形成的非活性复合物。它在456 nm处显示Soret峰，不结合CO，并被加入50 μ M铁氰化钾破坏。在其他6名受试者中测定了安替比林的清除率。当在醋竹桃霉素处理的第7天再次测量时，该清除率降低了45%。重复施用醋竹桃霉素明显诱导微粒体酶，产生无活性的细胞色素P-450 Fe（II）-代谢物复合物，并降低人体中安替比林的清除率。
Troleandomycin [a macrolide antibiotic] induces its own transformation into a metabolite forming an inactive complex with reduced cytochrome P-450 in rats. To determine whether similar effects occur in humans, hepatic microsomes from 6 untreated patients and 6 patients treated with troleandomycin, 2 g orally daily for 7 days, were studied. In the treated patients, NADPH-cytochrome c reductase activity was increased by 48%; total cytochrome P-450 concentration was also increased, but 33% of total cytochrome P-450 was complexed by a troleandomycin metabolite. The cytochrome P-450 Fe(II)-metabolite complex exhibited properties identical to those of the inactive complex formed in rats. It exhibited a Soret peak at 456 nm, did not bind CO and was destroyed by addition of 50 .mu.M potassium ferricyanide. The clearance of antipyrine was measured in 6 other subjects. This clearance was decreased by 45% when measured again on the 7th day of the troleandomycin treatment. Repeated administration of troleandomycin apparently induced microsomal enzymes, produced an inactive cytochrome P-450 Fe(II)-metabolite complex and decreased the clearance of antipyrine in humans.