Influence of amphotericin B treatment duration of hepatic microsomal enzyme function in rats.
The influence of amphotericin B on various cytochrome P450-dependent mixed-function oxidases, antipyrine clearance and glucose-6-phosphatase was investigated in rats treated daily with deoxycholate amphotericin B (3 mg/kg body weight, intravenously) either for 1 or 4 days. Enzyme activity was measured ex vivo in hepatic microsomes. Following amphotericin B plus deoxycholate application for day 1, ethoxycoumarin-O-deethylase activity decrease significantly whereas microsomal cytochrome P450 concentration, cytochrome c reductase activity, antipyrine clearance and glucose-6-phosphatase activity did not change significantly. In contrast, following application of amphotericin B plus deoxycholate for 4 days the cytochrome P450 concentration was reduced by 50% (p < 0.05) as well as ethoxycoumarin-O-deethylase activity, antipyrine clearance and glucose-6-phosphatase activity: ethoxycoumarin-O-deethylase 232 +/- 68 pmol/mg/min, control 442 +/- 99 pmol/mg/min (p < 0.01); antipyrine clearance 0.56 +/- 0.21 ml/min, control 0.96 +/- 0.18 ml/min (p < 0.01), and glucose-6-phosphatase 193 +/- 28 mU/mg, control 351 +/- 95 mU/mg (p < 0.05). Cytochrome c reductase activity did not decrease significantly. Besides an increase in cytochrome c reductase activity, sodium deoxycholate (a vehicle of amphotericin B) alone induced no significant changes. Microsomal protein related to liver wet weight was significantly reduced by 50% (p < 0.01) only in animals treated for 4 days with amphotericin B plus deoxycholate. The results show that a 1-day treatment of rats with amphotericin B decreases ethoxycoumarin-O-deethylase activity, whereas the hepatic microsomal cytochrome P450 content, cytochrome c reductase and glucose-6-phosphatase activity did not change. Amphotericin B given for 4 days significantly decreases hepatic microsomal enzyme function. The inhibitory effect of amphotericin B on hepatic cytochrome P450 may be due to inhibition of hepatic protein synthesis.
Inselmann
G
G
Medizinische Poliklinik, Universität Würzburg, Germany.
Voss
V
V
Kunigk
F
F
Heidemann
H
H
D000666:Amphotericin B / Q000008:administration & dosage*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage*; D000983:Antipyrine / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000935:Antifungal Agents; D000666:Amphotericin B; D006899:Mixed Function Oxygenases; D005952:Glucose-6-Phosphatase; D000983:Antipyrine