Effect of some indole derivatives on xenobiotic metabolism and xenobiotic-induced toxicity in cultured rat liver slices

In this study the effect of some indole derivatives on xenobiotic metaboliz ing enzymes and xenobiotic-induced toxicity has been examined in cultured p recision-cut liver slices from male Sprague-Dawley rats. While treatment of rat liver slices for 72 hours with 2-200 mu M of either indole-3-carbinol (I3C) or indole-3-acetonitrile (3-ICN) had little effect on cytochrome P-45 0 (CYP)-dependent enzyme activities, enzyme induction was observed after in vivo administration of I3C. The treatment of rat liver slices with 50 mu M 3,3'-diindolylmethane (DIM; a dimer derived from I3C under acidic conditio ns) for 72 hours resulted in a marked induction of CYP-dependent enzyme act ivities. DIM appears to be a mixed inducer of CYP in rat liver slices havin g effects on CYP1A, CYP2B and CYP3A subfamily isoforms. Small increases in liver slice reduced glutathione levels and glutathione S-transferase activi ty were also observed after DIM treatment. While affatoxin B-1 and monocrot aline produced a concentration-dependent inhibition of protein synthesis in 72-hour-cultured rat liver slices, cytotoxicity was markedly reduced in li ver slices cultured with 50 mu M DIM. These results demonstrate that cultur ed rat liver slices may be employed to evaluate the effects of chemicals de rived from cruciferous and other vegetables on CYP isoforms. In addition, l iver slices can also be utilized to examine the ability of such chemicals t o modulate xenobiotic-induced toxicity. Crown Copyright (C) 1999 Published by Elsevier Science Ltd. All rights received.