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Madyastha KM, Moorthy B: Pulegone mediated hepatotoxicity: evidence for covalent binding of R (+)-[14C] pulegone to microsomal proteins in vitro. Chem Biol Interact. 1989;72(3):325-33.
Incubation of R (+)-[14C] pulegone with rat liver microsomes in the presence of NADPH resulted in covalent binding of radioactive material to macromolecules. Covalent binding was much higher in phenobarbital-treated microsomes as compared to 3-methylcholanthrene treated or control microsomes. The Km and Vmax of covalent binding was 0.4 mM and 1.7 nmol min-1 mg-1, respectively. Covalent binding was drastically inhibited (93%) in the presence of piperonyl butoxide. Antibodies to phenobarbital-induced cytochrome P-450 and NADPH-cytochrome P-450 reductase inhibited covalent binding to an extent of 72% and 47%, respectively. Cysteine and semicarbazide also inhibited NADPH dependent binding of radiolabel from R (+)-[14C] pulegone to microsomal proteins. The results suggest the involvement of liver microsomal cytochrome P-450 in the bioactivation of R (+)-pulegone to reactive metabolite (s) which might be responsible for covalent binding to macromolecules resulting in toxicity. |
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