C. Fradette and P. du Souich Pages 257 - 271 ( 15 )
In the last three decades, numerous reports have shown that patients with chronic pulmonary disease and with heart failure with hypoxemia cleared drugs at a lower rate than healthy volunteers. As a consequence decreased clearance, drug toxicity is frequent in these patients. The reduction in drug clearance is due to a decrease in activity of cytochrome P450 isoforms, partly associated to the hypoxemia. With in vivo animal models, acute moderate hypoxia (PaO2 of around 35-50 mm Hg) reduces the clearance of drugs biotransformed by CYP1A1, CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP2E1, although hypoxia does not affect the clearance of drugs biotransformed by CYP3A6. Ex vivo and in vitro experiments demonstrate that hypoxia down-regulates CYP1A1, CYP1A2, CYP2B6, CYP2C9 and CYP2C19, decrease preceded by a reduction in activity. On the other hand, acute moderate hypoxia up-regulates CYP3A6. The changes in protein expression are preceded by modifications in the mRNA coding for the proteins. The effect of hypoxia on hepatic cytochrome P450 is carried out by serum mediators, e.g. interferon-γ, interleukin-1β, and interleukin-2 are responsible for the decrease in activity and in expression of cytochrome P450 isoforms, and erythropoietin accounts for the increase in CYP3A6. Probably several mechanisms underlie and contribute to the decrease in activity and down-regulation of cytochrome P450 isoforms by hypoxia, e.g. reducing potentiation factors, inducing repressor elements and activating negative regulatory elements. The up-regulation of CYP3A6 implies a PTK- and p42 / 44MAPK-dependent stabilization / activation, nuclear translocation of HIF-1 and AP-1, binding to CYP3A6 promoter, and transactivation of the gene to induce CYP3A6 expression.
cytochrome p450, hypoxia, catalytic activity, expression, signal transduction pathways, hif-1, ap-1, reactive oxygen intermediate
Department of Pharmacology, Faculty of Medicine, University of Montreal, P.O. Box 6128, Stat. Centre- Ville, Montreal, Quebec, Canada.