PT  - JOURNAL ARTICLE
AU  - Thulasiram, Hirekodathakallu V.
AU  - Gadad, Andanappa K.
AU  - Madyastha, Madhava K.
TI  - Role of C-5 Chiral Center in<em>R</em>-(+)-Pulegone-Mediated Hepatotoxicity: Metabolic Disposition and Toxicity of 5,5-Dimethyl-2-(1-Methylethylidene)-Cyclohexanone in Rats
DP  - 2000 Jul 01
TA  - Drug Metabolism and Disposition
PG  - 833--844
VI  - 28
IP  - 7
4099  - http://dmd.aspetjournals.org/content/28/7/833.short
4100  - http://dmd.aspetjournals.org/content/28/7/833.full
SO  - Drug Metab Dispos2000 Jul 01; 28
AB  - 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 metabolites 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-dimethyl-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 phenobarbital (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 μM. 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 aminopyrineN-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 CCl4 (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. The American Society for Pharmacology and Experimental Therapeutics