Effect of some Indole Derivatives on Xenobiotic Metabolism and Xenobiotic-induced Toxicity in Cultured Rat Liver Slices

• Published in: Food and chemical toxicology 1999-06, Vol.37 (6), p.609-618
• Main Authors: Renwick, A.B., Mistry, H., Barton, P.T., Mallet, F., Price, R.J., Beamand, J.A., Lake, B.G.
• Format: Article
• Language: English
• Subjects: 3,3-diindolylmethane; 7-ethoxyredorufin o-deethylase; Aflatoxin B1 - toxicity; aflatoxins; Animals; Anticarcinogenic Agents - pharmacology; Biological and medical sciences; Carcinogenicity Tests; Carcinogens - toxicity; Chemical mutagenesis; cytochrome P-450; Cytochrome P-450 Enzyme System - metabolism; cytotoxicity; Drug Interactions; enzyme activity; enzyme induction in vitro; General aspects. Methods; glutathione; glutathione transferase; In Vitro Techniques; indole-3-acetonitrile; indole-3-methanol; indoles; Indoles - pharmacology; inhibition; liver; Liver - drug effects; Liver - enzymology; Liver - metabolism; Male; Medical sciences; microsomes; Monocrotaline - toxicity; precision-cut rat liver slices; pyrrolizidine alkaloids; rat liver; Rats; Rats, Sprague-Dawley; stimulation; Toxicology; unspecific monooxygenase; Xenobiotics - metabolism; Xenobiotics - toxicity
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/S0278-6915(99)00026-5

In this study the effect of some indole derivatives on xenobiotic metabolizing enzymes and xenobiotic-induced toxicity has been examined in cultured precision-cut liver slices from male Sprague–Dawley rats. While treatment of rat liver slices for 72 hours with 2–200 μ m of either indole-3-carbinol (I3C) or indole-3-acetonitrile (3-ICN) had little effect on cytochrome P-450 (CYP)-dependent enzyme activities, enzyme induction was observed after in vivo administration of I3C. The treatment of rat liver slices with 50 μ m 3,3′-diindolylmethane (DIM; a dimer derived from I3C under acidic conditions) for 72 hours resulted in a marked induction of CYP-dependent enzyme activities. DIM appears to be a mixed inducer of CYP in rat liver slices having effects on CYP1A, CYP2B and CYP3A subfamily isoforms. Small increases in liver slice reduced glutathione levels and glutathione S-transferase activity were also observed after DIM treatment. While aflatoxin B 1 and monocrotaline produced a concentration-dependent inhibition of protein synthesis in 72-hour-cultured rat liver slices, cytotoxicity was markedly reduced in liver slices cultured with 50 μ m DIM. These results demonstrate that cultured rat liver slices may be employed to evaluate the effects of chemicals derived from cruciferous and other vegetables on CYP isoforms. In addition, liver slices can also be utilized to examine the ability of such chemicals to modulate xenobiotic-induced toxicity.