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 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 O2 of 10% (mean PaO2 of 34 mmHg). Hypoxia decreased theophylline metabolic clearance (ClM) 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. 2 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 ClM, 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. 3 Pre-treatment with 3MC augmented the ClM 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. 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 restores P450 activity to near normal values. On the other hand, pre-treatment with 3MC prevents the hypoxia-induced depression of the P450.
Kurdi
J
J
Department of Pharmacology, Faculty of Medicine, C.P. 6128, Succ. 'Centre-ville', Montréal, Québec, Canada H3C 3J7.
Maurice
H
H
El-Kadi
A O
AO
Ong
H
H
Dalkara
S
S
Bélanger
P M
PM
Souich
P
P
D000818:Animals; D001059:Apoproteins / Q000378:metabolism; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D000860:Hypoxia / Q000201:enzymology*; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology*; D007509:Irritants; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011817:Rabbits; D013806:Theophylline / Q000378:metabolism / Q000494:pharmacology; D014425:Turpentine
D001059:Apoproteins; D007509:Irritants; D010726:Phosphodiesterase Inhibitors; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D013806:Theophylline; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; C100638:cytochrome P-450 CYP3A6 (rabbit); D014425:Turpentine