21-Aminosteroids prevent the down-regulation of hepatic cytochrome P450 induced by hypoxia and inflammation in conscious rabbits

1 This study was conducted to assess whether a 21-aminosteroid, U74389G, co uld prevent the down-regulation of hepatic cytochrome P450 (P450) induced b y acute moderate hypoxia or an inflammatory reaction. 2 The rabbits of two groups (n = 6 per group) were subjected to acute moder ate hypoxia (PaO2 approximate to 35 mmHg), one pre-treated with U74389G (3 mg kg(-1) i.v. every 6 h, for 48 h). The rabbits of two other groups receiv ed 5 ml of turpentine s.c., one of them being pre-treated with U74389G (3 m g kg(-1) i.v. every 6 h, for 72 h). The kinetics of theophylline (2.5 mg kg (-1)) were assessed to evaluate the activity of the P450. Once the rabbits were sacrificed, the P450 content and the amount of thiobarbituric acid rea ctive substances (TBARS). a marker of lipid peroxidation, were estimated in the liver. 3 Compared with control rabbits, hypoxia and inflammation increased theophy lline plasma concentrations. as a result of a decrease in theophylline syst emic clearance (P < 0.05). Both experimental conditions reduced hepatic con tent of P450 by 40-50% (P < 0.05) and increased the amount of hepatic TBARS by around 50% (P < 0.05). Pre-treatment with U74389G prevented the hypoxia - and inflammation-induced decrease in theophylline systemic clearance, the down-regulation of hepatic P450, and the increase in liver TBARS. 4 It is concluded that in the rabbit, U74389G prevents hepatic P450 depress ion produced by acute moderate hypoxia and a turpentine-induced inflammator y reaction, possibly by eliciting a radical quenching antioxidant activity.