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Role of C-5 chiral center in R-(+)-pulegone-mediated hepatotoxicity: Metabolic disposition and toxicity of 5,5-dimethyl-2-(1-methylethylidene)-cyclohexanone in rats

Thulasiram, Hirekodathakallu V and Gadad, Andanappa K and Madyastha, Madhava K (2000) Role of C-5 chiral center in R-(+)-pulegone-mediated hepatotoxicity: Metabolic disposition and toxicity of 5,5-dimethyl-2-(1-methylethylidene)-cyclohexanone in rats. In: Drug Metabolism and Disposition, 28 (7). pp. 833-844.

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Abstract

Metabolic disposition of 5,5-dimethyl-2-(1-methylethylidene)-cyclohexanone (I) was examined in rats. Compound (I) was administered orally (250 mg/kg of body weight/day) to rats for 5 days. The following urinary met abolites were isolated and identified: 4,5,6,7-tetrahydro-3,6,6-trimethylbenzofuran (III), 3,3-dimethylcyclohexanone (VI), 5,5-dimethyl-3-hydroxy-2-(1-methylethylidene)-cyclohexanone (X), 5,5-d methyl-2-(1-hydroxymethylethyl)-cyclohexanone (IX), 3-hydroxy-5-hydroxymethyl-5-methyl-2-(1-methylethylidene)-cyclohexanone (XI), 5,6-dihydro-3,6,6-trimethyl-2(4H)-benzofuranone (VIII), and 5,5-dimethyl-3-hydroxy-2-(1-carboxy ethylidene)-cyclohexanone (XIII). Incubation of compound (I) with pheno arbital (PB)-induced rat liver microsomes in the presence of NADPH resulted in the formation of a metabolite, tentatively identified as a furanoterpene (III) based on proton magnetic resonance, gas chromatography, and gas chromatography-mass spectroscopy analyses. The formation of III was inhibited to a significant extent by carbon monoxide, metyrapone, SKF 525-A, and cytochrome c, suggesting the participation of PB-induced microsomal cytochrome P-450 system in the conversion of I to III. Compound I gave type I spectral change in the PB-induced liver microsomes and the dissociation constant (Ks) for I was 38.5 $\mu M$. Intraperitoneal administration of a single dose (250 mg/kg) of I to rats resulted in 26, 23, and 41% decreases in the levels of cytochrome P-450, glucose-6-phosphatase, and aminopyrine N-demethylase, respectively, at the end of 24 h. During this period, a 11-fold increase in serum glutamate pyruvate transaminase level was also observed. However, a decrease in the level of cytochrome P-450 and glucose-6-phosphatase, and an increase in serum glutamate pyruvate transaminase values were comparatively more pronounced when R-(+)-pulegone (250 mg/kg) or $CCl_4$ (0.6 ml/kg) was administered to rats. Pretreatment of rats with PB potentiated the hepatotoxicity caused by I, whereas pretreatment with 3-methylcholanthrene protected from it. This suggests that PB-induced cytochrome P-450-catalyzed reactive metabolites may be responsible for the toxic effects caused by I.

Item Type: Journal Article
Additional Information: Copyright of this article belongs to The American Society for Pharmacology and Experimental Therapeutics
Keywords: Pharmacology;Toxicology
Department/Centre: Division of Chemical Sciences > Organic Chemistry
Date Deposited: 17 Oct 2007
Last Modified: 19 Sep 2010 04:40
URI: http://eprints.iisc.ernet.in/id/eprint/12102

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