DRUG-METABOLIZING-ENZYMES IN RAT-LIVER MYOFIBROBLASTS

The myofibroblast is considered to he a key component in the pathogene sis of hepatic fibrosis. There is a need for therapeutic intervention in hepatic fibrosis, and, to date, the number of efficacious anti-fibr otic 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 pen toxifylline in an experimental model of hepatic fibrosis. Evidence sug gests that, in addition to pentoxifylline itself, at least two of the metabolites of pentoxifylline are of therapeutic interest. We have rep orted that one of these metabolites (M-1) has a biological activity si milar to that of its parent drug. The second metabolite (M-1R) has bee n reported to be more potent than the parent drug. Recent evidence sug gests that inhibition of cytochrome P450 1A2 (CYP1PL2) results in high er levels of pentoxifylline and M-1 and may be responsible for the pro duction of the novel, potent metabolite (M-1R). We therefore investiga ted whether the myofibroblast, the cell with a crucial role in fibrosi s, contains drug-metabolizing enzymes and thus may play a critical rol e in the anti-fibrotic actions of pentoxifylline. Our results showed t hat myofibroblasts contain aryl hydrocarbon hydroxylase activity, etho xyresorufin O-deethylase activity, and methoxyresorufin O-demethylase activity. The results presented here also indicate that aryl hydrocarb on hydroxylase and methoxyresorufin O-demethylase activities can be in creased by treatment of cells with dibenzanthracene, an inducer of CYP 1A activities. (C) 1998 Elsevier Science Inc.