Effect of amphotericin B on hepatic cytochrome P-450 and glucose-6-phosphatase in the rat

Abstract

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 μg/ml) and its vehicle, sodium deoxycholate (0–410 μg/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 < 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 < 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.