Effect of hypoxia alone or combined with inflammation and 3-methylcholanthrene on hepatic cytochrome P450 in conscious rabbits

1 To investigate the effect of moderate hypoxia alone or combined with an i nflammatory reaction or after 3-methylcholanthrene (3MC) pre-treatment on c ytochrome P450 (P450), conscious rabbits were exposed for 24 h to a fractio nal concentration of inspired O-2 of 10% (mean PaO2 of 34 mmHg). Hypoxia de creased theophylline metabolic clearance (Cl-M) from 1.73 +/- 0.43 to 1.48 +/- 0.13 ml min(-1) kg(-1) (P < 0.05), and reduced (P < 0.05) the formation clearance of theophylline metabolites, 3-methylxanthine (3MX), 1-methyluri c acid (1MU) and 1,3-dimethyluric acid (1,3DMU). Hypoxia reduced the amount of CYP1A1 and 1A2 but increased CYP3A6 proteins. 2 Turpentine-induced inflammatory reaction reduced (P < 0.05) the formation clearance of 3MX, 1MU, and I,3DMU, and diminished the amount of CYP1A1, 1A 2 and 3A6 proteins. However, when combined with hypoxia, inflammation parti ally prevented the decrease in Cl-M, especially by impeding the reduction o f 1,3DMU. The amount of CYP1A1 and 1A2 remained reduced but the amount of C YP3A6 protein returned to normal values. 3 Pre-treatment with 3MC augmented the Cl-M by 114% (P < 0.05) due to the i ncrease in the formation clearance of 3MX, 1MU and 1,3DMU. 3MC treatment in creased the amount of CYP1A1 and 1A2 proteins. Pre-treatment with 3MC preve nted the hypoxia-induced decrease in amount and activity of the P450. 4 It is concluded that acute moderate hypoxia and an inflammatory reaction individually reduce the amount and activity of selected apoproteins of the P450. However, the combination of hypoxia and the inflammatory reaction res tores P450 activity to near normal values. On the other hand, pretreatment with 3MC prevents the hypoxia-induced depression of the P450.