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 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.
Footnotes
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Send reprint requests to: Prof. K. M. Madyastha, Bio-organic Section, Department of Organic Chemistry, Indian Institute of Science, Bangalore-560 012, India. E-mail:kmm{at}orgchem.iisc.ernet.in
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This work was supported in part by Jawaharlal Nehru Center for Advanced Scientific Research (Bangalore), CSIR (New Delhi), and DBT (New Delhi). H.V.T. is the recipient of a research fellowship from IISc, Bangalore.
- Abbreviations used are::
- 3-MC
- 3-methylcholanthrene
- GC
- gas chromatography
- IR
- infrared
- MS
- mass spectroscopy
- PMR
- proton magnetic resonance
- Rf
- relative front
- Rt
- retention time
- TLC
- thin layer chromatography
- PB
- phenobarbital
- SGPT
- serum glutamate pyruvate transaminase
- HRMS
- high resolution mass spectral
- Received November 29, 1999.
- Accepted April 12, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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