Phenotype of hepatic xenobiotic metabolizing enzymes and CYP450 isoforms of sanguinarine treated rats: effect of P450 inducers on its toxicity.
Catalytic and immunochemical activities of cytochrome P450 (CYP) isoforms were investigated in argemone alkaloid, sanguinarine (SAN) intoxicated rats, pre-treated with different CYP inducers. SAN treated control (CON) and ethanol (ET), 3- methylcholantherene (MC) or dexamethasone (DEX) pre-exposed rats, resulted in 48, 64, 47 and 33% decrease in CYP content. SAN exposure to CON, and DEX, MC or ET pre-treated animals caused a decrease (22-37%) in glutathione-S-transferase (GST) activity, however, quinone reductase (QR) activity decreased (26-45%) in the MC pre-exposed group. Similarly, western-blot analysis of hepatic CYP1A1 and CYP1A2 showed a decrease (27-37%) in MC pre-treated SAN exposed animals. Further, a decrease in mortality in the SAN+MC (25%) group compared to SAN treated animals was also observed. The results suggest that inhibition of CYP 1A1, 1A2, 2D1, 2E1, 3A1, and Phase II enzymes by SAN augments its toxicity, whereas attenuation of SAN toxicity by MC may be due to removal of parent compound/metabolites from the body.
Food Toxicology Division, Indian Institute of Toxicology Research (Formerly, Industrial Toxicology Research Centre), Council of Scientific and Industrial Research, Lucknow, India.
Naveen Reddy
NR
Eruvaram
Mukul
M
Das
D000818:Animals; D031674:Argemone / Q000737:chemistry; D053119:Benzophenanthridines / Q000032:analysis / Q000302:isolation & purification / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D015786:Cytochromes b5 / Q000096:biosynthesis; D004790:Enzyme Induction; D005982:Glutathione Transferase / Q000096:biosynthesis; D008658:Inactivation, Metabolic / Q000235:genetics*; D007527:Isoenzymes; D007546:Isoquinolines / Q000032:analysis / Q000302:isolation & purification / Q000633:toxicity*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis; D009251:NADPH-Ferrihemoprotein Reductase / Q000096:biosynthesis; D010938:Plant Oils / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar
D053119:Benzophenanthridines; D007527:Isoenzymes; D007546:Isoquinolines; D010938:Plant Oils; C030610:argemone oil; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; C005705:sanguinarine; D009251:NADPH-Ferrihemoprotein Reductase; D016660:NAD(P)H Dehydrogenase (Quinone); D005982:Glutathione Transferase