Drug-metabolizing enzymes in rat liver myofibroblasts.
The myofibroblast is considered to be a key component in the pathogenesis of hepatic fibrosis. There is a need for therapeutic intervention in hepatic fibrosis, and, to date, the number of efficacious anti-fibrotic drugs is negligible. At best, the current therapeutic modalities reduce liver enzymes, an indicator of liver damage, but cannot reduce or prevent fibrosis. We have described the anti-fibrotic effect of pentoxifylline in an experimental model of hepatic fibrosis. Evidence suggests that, in addition to pentoxifylline itself, at least two of the metabolites of pentoxifylline are of therapeutic interest. We have reported that one of these metabolites (M-1) has a biological activity similar to that of its parent drug. The second metabolite (M-1R) has been reported to be more potent than the parent drug. Recent evidence suggests that inhibition of cytochrome P450 1A2 (CYP1A2) results in higher levels of pentoxifylline and M-1 and may be responsible for the production of the novel, potent metabolite (M-1R). We therefore investigated whether the myofibroblast, the cell with a crucial role in fibrosis, contains drug-metabolizing enzymes and thus may play a critical role in the anti-fibrotic actions of pentoxifylline. Our results showed that myofibroblasts contain aryl hydrocarbon hydroxylase activity, ethoxyresorufin O-deethylase activity, and methoxyresorufin O-demethylase activity. The results presented here also indicate that aryl hydrocarbon hydroxylase and methoxyresorufin O-demethylase activities can be increased by treatment of cells with dibenzanthracene, an inducer of CYP1A activities.
Peterson
T C
TC
Department of Medicine, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
Rowden
G
G
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001551:Benz(a)Anthracenes / Q000494:pharmacology; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005347:Fibroblasts / Q000201:enzymology; D008099:Liver / Q000166:cytology / Q000201:enzymology*; D008106:Liver Cirrhosis, Experimental / Q000201:enzymology; D010088:Oxidoreductases / Q000378:metabolism*; D010431:Pentoxifylline / Q000494:pharmacology; D051381:Rats
D001551:Benz(a)Anthracenes; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; C076307:methoxyresorufin-O-demethylase; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D010431:Pentoxifylline