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Stereoselective hydroxylation of 4-methyl-2-cyclohexenone in rats: its relevance to R-(+)-pulegone-mediated hepatotoxicity

Madyastha, KM and Raj, Paul C (2002) Stereoselective hydroxylation of 4-methyl-2-cyclohexenone in rats: its relevance to R-(+)-pulegone-mediated hepatotoxicity. In: Biochemical and Biophysical Research Communications, 297 (2). pp. 202-205.

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Abstract

R-(+)-Pulegone, a monoterpene ketone, is a potent hepatotoxin. One of the major metabolites of pulegone has been shown to be p-cresol, a glutathione depletor and a known toxin. Allylic hydroxylation of 4-methyl-2-cyclohexenone results in the formation of p-cresol. The present study documents for the first time the involvement of cytochrome P-450 system and the stereochemical preference in this hydroxylation reaction. Incubation of PB-induced rat liver microsomes as well as reconstituted PB-induced cytochrome P-450 system with $\pm4-methyl-2-cyclohexenone$ in the presence of NADPH and $O_2$ resulted in the formation of 4-hydroxy-4-methyl-2-cyclohexenone and p-cresol. From the assay mixture, the unreacted substrate, viz., 4-methyl-2-cyclohexenone was isolated and purified and its optical rotation was found to be 2.2 (in $CHCl_3$). The observed enantiomeric excess in the recovered substrate was further confirmed by circular dichroism (CD) studies. The CD spectrum has a peak at 292 nm and a trough at 270 nm. The enantiomeric excess in the recovered substrate indicates that the hydroxylation at C-4 position is stereoselective. The significance of these results with respect to pulegone-mediated hepatotoxicity is discussed.

Item Type: Journal Article
Additional Information: Copyright of this article belongs to Elsevier.
Keywords: R-(+)-Pulegone;4-Methyl-2-cyclohexenone;p-Cresol;Stereoselective hydroxylation;Cytochrome P-450 system;Hepatotoxicity;Optical rotation;CD spectrum
Department/Centre: Division of Chemical Sciences > Organic Chemistry
Date Deposited: 24 Oct 2007
Last Modified: 19 Sep 2010 04:40
URI: http://eprints.iisc.ernet.in/id/eprint/12335

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