Possible role of the acetone-inducible cytochrome P-450IIE1 in the metabolism and hepatotoxicity of thiobenzamide

• Published in: Archives of toxicology Vol. 64; no. 2; p. 122
• Main Authors: Chieli, E, Saviozzi, M, Puccini, P, Longo, V, Gervasi, P G
• Format: Journal Article
• Language: English
• Published: Germany 01.01.1990
• Subjects: Acetone - pharmacology; Alanine Transaminase - blood; Amides - metabolism; Animals; Chemical and Drug Induced Liver Injury - enzymology; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - pathology; Cytochrome P-450 Enzyme System - biosynthesis; Cytochrome P-450 Enzyme System - physiology; Enzyme Induction - drug effects; In Vitro Techniques; Isoenzymes - biosynthesis; Isoenzymes - physiology; Kinetics; Male; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Oxidation-Reduction; Rats; Rats, Inbred Strains; Thioamides - metabolism; Thioamides - toxicity
• ISSN: 0340-5761
• DOI: 10.1007/BF01974397

The effect of acetone pretreatment (5% in drinking water for 10 days on rat liver metabolism and toxicity of thiobenzamide (TB) was investigated. Hepatic microsomes from acetone-pretreated rats showed a significant increase of TB-S-oxidation rate which, on the basis of selective thermal inactivation of FAD-containing monooxygenase (FADM), appeared dependent only on cytochrome P-450. Furthermore, TB was able to competitively inhibit acetone hydroxylase (AcH), an enzymatic reaction highly specific for the P-450IIE1 isozyme. Acetone pretreatment of rats also produced an exacerbation of liver damage induced by acute administration of TB (150 mg/kg), as judged by the extent of liver necrosis and serum alanine-amino transferase (ALAT) activities. Coadministration of acetone with TB reduced on the other hand the extent of liver damage. The findings suggest that P-450 species induced by acetone, and in particular the P-450IIE1 isozyme, could be involved in the biotransformation of TB.