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Effect of hypoxia alone or combined with inflammation and 3‐methylcholanthrene on hepatic cytochrome P450 in conscious rabbits
Author(s) -
Kurdi J,
Maurice H,
ElKadi A O S,
Ong H,
Dalkara S,
Bélanger P M,
Du Souich P
Publication year - 1999
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702795
Subject(s) - hypoxia (environmental) , cytochrome p450 , theophylline , chemistry , medicine , endocrinology , methylcholanthrene , inflammation , metabolism , oxygen , biochemistry , carcinogen , organic chemistry
To investigate the effect of moderate hypoxia alone or combined with an inflammatory reaction or after 3‐methylcholanthrene (3MC) pre‐treatment on cytochrome P450 (P450), conscious rabbits were exposed for 24 h to a fractional concentration of inspired O 2 of 10% (mean PaO 2 of 34 mmHg). Hypoxia decreased 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‐methyluric acid (1MU) and 1,3‐dimethyluric acid (1,3DMU). Hypoxia reduced the amount of CYP1A1 and 1A2 but increased CYP3A6 proteins. Turpentine‐induced inflammatory reaction reduced ( P <0.05) the formation clearance of 3MX, 1MU, and 1,3DMU, and diminished the amount of CYP1A1, 1A2 and 3A6 proteins. However, when combined with hypoxia, inflammation partially prevented the decrease in Cl M , especially by impeding the reduction of 1,3DMU. The amount of CYP1A1 and 1A2 remained reduced but the amount of CYP3A6 protein returned to normal values. Pre‐treatment with 3MC augmented the Cl M by 114% ( P <0.05) due to the increase in the formation clearance of 3MX, 1MU and 1,3DMU. 3MC treatment increased the amount of CYP1A1 and 1A2 proteins. Pre‐treatment with 3MC prevented the hypoxia‐induced decrease in amount and activity of the P450. 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 restores P450 activity to near normal values. On the other hand, pre‐treatment with 3MC prevents the hypoxia‐induced depression of the P450.British Journal of Pharmacology (1999) 128 , 365–373; doi: 10.1038/sj.bjp.0702795