Effect of naturally occurring plant phenolics on the induction of drug metabolizing enzymes by o-toluidine

• Published in: Toxicology (Amsterdam) 2003-04, Vol.186 (1), p.67-77
• Main Authors: Szaefer, Hanna, Jodynis-Liebert, Jadwiga, Cichocki, Michał, Matuszewska, Arleta, Baer-Dubowska, Wanda
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Biotransformation - drug effects; Caffeine - blood; Caffeine - pharmacokinetics; Caffeine metabolism; Carcinogenesis, carcinogens and anticarcinogens; Carcinogens - toxicity; Chemical agents; Cytochrome P-450 CYP1A1 - antagonists & inhibitors; Cytochrome P-450 CYP1A1 - biosynthesis; Cytochrome P-450 CYP1A1 - metabolism; Cytochrome P-450 CYP2B1 - antagonists & inhibitors; Cytochrome P-450 CYP2B1 - biosynthesis; Cytochrome P-450 CYP2B1 - metabolism; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - biosynthesis; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450; Ellagic acid; Ellagic Acid - pharmacology; Enzyme Induction - drug effects; Glutathione Transferase - metabolism; Hydrolyzable Tannins - pharmacology; Hydroxybenzoates - pharmacology; Kidney - drug effects; Kidney - enzymology; Kidney - metabolism; Liver - drug effects; Liver - enzymology; Liver - metabolism; Male; Medical sciences; o-Toluidine; Oxidoreductases - antagonists & inhibitors; Oxidoreductases - biosynthesis; Oxidoreductases - metabolism; Protocatechuic acid; Rats; Rats, Wistar; Tannic acid; Theobromine - metabolism; Theophylline - metabolism; Toluidines - toxicity; Tumors
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/S0300-483X(02)00615-7

Plant phenolics modify the metabolic activation of several carcinogens, including aromatic amines. In this study, we have evaluated the effects of three structurally diversified plant phenolics, protocatechuic acid (PCA), tannic acid (TA) and ellagic acid (EA) on cytochrome P450-dependent enzymes and glutathione S-transferase (GST) activities after oral administration alone or in combination with o-toluidine in rat liver and kidney. Protocatechuic and ellagic acids significantly decreased the activities of ethoxy- (EROD), methoxy- (MROD) and penthoxyresorufin (PROD) dealkylases in liver. In kidney, all phenolics inhibited only the activity of PROD. Enzyme modulation in liver correlated with CA metabolism measured in plasma. Treatment of rats with ellagic acid 1 h before o-toluidine administration diminished the activities of all hepatic alkoxyresorufine dealkylases induced by o-toluidine but increased renal EROD. In contrast to EA, protocatechuic and tannic acids increased the activities of P450-dependent enzymes in liver. All phenolics administered in combination with o-toluidine increased the activity of GST, which was reduced after the treatment with o-toluidine alone. In addition, CA metabolism in plasma resulting from oral treatment with CA was measured. The formation of CA metabolites was reduced by PCA and EA, and the metabolism of CA induced by o-toluidine was depressed by administration of all three phenolics. Our results indicate that plant phenolics, especially EA, may modulate the genotoxic effects of o-toluidine by modifying pathways leading to the formation of its reactive metabolite. Moreover, as the result of CYP1A modification these compounds may affect the metabolism of CA.