Possible role of the acetone-inducible cytochrome P-450IIE1 in the metabolism and hepatotoxicity of thiobenzamide.
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.
Chieli
E
E
Istituto di Patologia Generale dell'Università di Pisa, Scuola Medica, Italy.
Saviozzi
M
M
Puccini
P
P
Longo
V
V
Gervasi
P G
PG
D000096:Acetone / Q000494:pharmacology*; D000410:Alanine Transaminase / Q000097:blood; D000577:Amides / Q000378:metabolism*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000502:physiology*; D004790:Enzyme Induction / Q000187:drug effects; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000096:biosynthesis / Q000502:physiology*; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D013854:Thioamides / Q000378:metabolism* / Q000633:toxicity
D000577:Amides; D007527:Isoenzymes; D013854:Thioamides; D000096:Acetone; C015539:thiobenzamide; D003577:Cytochrome P-450 Enzyme System; D000410:Alanine Transaminase