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Pulegone mediated hepatotoxicity: Evidence for covalent binding of R(+)-$[^{14}C]$pulegone to microsomal proteins in vitro

Madyastha, KM and Moorthy, B (1989) Pulegone mediated hepatotoxicity: Evidence for covalent binding of R(+)-$[^{14}C]$pulegone to microsomal proteins in vitro. In: Chemico-Biological Interactions, 72 (3). pp. 325-33.

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Abstract

Incubation of R(+)-$[^{14}C]$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 $K_m$ and $V_{max}$ 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(+)-$[^{14}C]$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.

Item Type: Journal Article
Additional Information: The copyright belongs to Elsevier Science Publishers Ireland Ltd.
Keywords: Pulegone; Microsomal proteins; Covalent binding
Department/Centre: Division of Chemical Sciences > Organic Chemistry
Date Deposited: 11 Dec 2007
Last Modified: 19 Sep 2010 04:41
URI: http://eprints.iisc.ernet.in/id/eprint/12461

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