Heidemann H, Holzlöhner U, Heydemann J, Freitag T, Inselmann G
I. Medizinische Klinik, Christian-Albrechts-Universität, Kiel, Federal Republic of Germany.
J Hepatol. 1992 Mar;14(2-3):300-4. doi: 10.1016/0168-8278(92)90174-n.
The effect of amphotericin B on hepatic microsomal cytochrome P-450 (P-450) concentration was measured in vitro, in vivo and ex vivo in the rat. In vitro, both amphotericin B (0-500 micrograms/ml) and its vehicle, sodium deoxycholate (0-410 micrograms/ml), caused similar dose-dependent decreases of P-450 concentrations and glucose-6-phosphatase activity. Intravenous amphotericin B (3 mg/kg) given daily for 3 days decreased antipyrine clearance from control values of 1.24 +/- 0.24 ml/min to 0.67 +/- 0.12 ml/min (p less than 0.001); whereas antipyrine clearance was unchanged by sodium deoxycholate. The P-450 concentration on the third day was reduced from 0.74 +/- 0.14 nmol/mg protein in control rats to 0.33 +/- 0.09 nmol/mg protein in rats treated with amphotericin B (p less than 0.001). Sodium deoxycholate had no effect on P-450 concentration. In contrast, amphotericin B had no effect on either antipyrine clearance or P-450 concentration following enzyme induction by phenobarbital. Amphotericin B had no effect on microsomal glucose-6-phosphatase activity in vivo. Neither amphotericin B nor sodium deoxycholate induced lipid peroxidation, measured as malondialdehyde production. These results show that amphotericin B decreases hepatic cytochrome P-450 content and function in the rat. These effects can not be observed in the enzyme induced state. Amphotericin B has no effect on glucose-6-phosphatase in vivo, the key enzyme of the gluconeogenesis, indicating selective effects on hepatic microsomal function.
在大鼠体内、体外和离体状态下测定了两性霉素B对肝微粒体细胞色素P-450（P-450）浓度的影响。在体外，两性霉素B（0 - 500微克/毫升）及其溶媒脱氧胆酸钠（0 - 410微克/毫升）均引起P-450浓度和葡萄糖-6-磷酸酶活性呈相似的剂量依赖性降低。每日静脉注射两性霉素B（3毫克/千克），连续3天，安替比林清除率从对照值1.24±0.24毫升/分钟降至0.67±0.12毫升/分钟（p＜0.001）；而脱氧胆酸钠对安替比林清除率无影响。第三天时，对照大鼠的P-450浓度为0.74±0.14纳摩尔/毫克蛋白，经两性霉素B治疗的大鼠降至0.33±0.09纳摩尔/毫克蛋白（p＜0.001）。脱氧胆酸钠对P-450浓度无影响。相比之下，苯巴比妥诱导酶活性后，两性霉素B对安替比林清除率或P-450浓度均无影响。两性霉素B在体内对微粒体葡萄糖-6-磷酸酶活性无影响。以丙二醛生成量衡量，两性霉素B和脱氧胆酸钠均未诱导脂质过氧化。这些结果表明，两性霉素B可降低大鼠肝脏细胞色素P-450含量及功能。在酶诱导状态下未观察到这些效应。两性霉素B对体内糖异生的关键酶葡萄糖-6-磷酸酶无影响，表明其对肝微粒体功能具有选择性作用。
