Abstract
R-(+)-Pulegone, a monoterpene ketone, is a potent hepatotoxin. The present study was designed to evaluate whether the reduction of the ring size in R-(+)-pulegone would affect its mode of metabolism and its hepatotoxic potential. Metabolic fate ofR-(+)-4-methyl-2-(1-methylethylidene)-cyclopentanone (I) and 5-methyl-2-(1-methylethylidene)-cyclopentanone (dl-camphorone; II) were examined in rats. Compounds I and II were administered orally (250 mg/kg of b.wt./day) to rats for 5 to 7 days. The following metabolites were isolated and identified from the urine of rats dosed with I: 3-methyl-5-(1-methylethylidene)-cyclopent-2-enone (Ie), Z-4-methyl-2-(1-hydroxymethylethylidene)-cyclopentanone (Ib), E-4-methyl-2-(1-hydroxymethylethylidene)-cyclopentanone (Ia), 3-hydroxy-4-methyl-2-(1-methylethylidene)-cyclopentanone (If), 4-hydroxy-4-methyl-2-(1-methylethylidene)-cyclopentanone (Ic), and E-4-methyl-2-(1-carboxyethylidene)-cyclopentanone (Id). Phenobarbital (PB)-induced rat liver microsomes in the presence of NADPH transformed compound I into metabolites, which were identified as Ia, Ib, Ic, Ie, and If. The following urinary metabolites were isolated and identified from compound II: 5-hydroxy-5-methyl-2-(1-methylethylidene)-cyclopentanone (IIc), 5-hydroxy-5-methyl-2-(1-methylethyl)-cyclopentanone (IIg), Z-5-methyl-2-(1-hydroxymethylethylidene)-cyclopentanone (IIb), 5-methyl-2-(1-hydroxymethylethyl)-cyclopentanone (IIf), E-5-methyl-2-(1-hydroxymethylethylidene)-cyclopentanone (IIa), E-5-methyl-2-(1-carboxyethylidene)-cyclopentanone (IId), and 5-methyl-2-(1-carboxyethyl)-cyclopentanone (IIe). PB-induced rat liver microsomes in the presence of NADPH were shown to transform compound II to IIa, IIb, and IIc. Studies carried out in vitro demonstrated that hydroxylation at the tertiary carbon atom or oxidation of the isopropylidene methyl groups in II can be specifically blocked through structural modifications as seen in compounds 2,2-dimethyl-5-(1-methylethylidene)-cyclopentanone (III) and 5-methyl-2-(1-ethyl-1-propylidene)-cyclopentanone (IV). Similar observation was also made when isopropylidene methyl groups inR-(+)-pulegone were replaced by ethyl groups. Intraperitoneal administration of a single dose (250 mg/kg) of I and II to rats did not elicit hepatotoxicity as judged by serum alanine aminotransaminase levels and liver microsomal drug metabolizing enzyme activities.
Footnotes
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Send reprint requests to: Professor Madhava K. 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 study was supported by CSIR (New Delhi). H.V.T. received a research fellowship from IISc, Bangalore, India.
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1 Abbreviations used are: PB, phenobarbital; IR, infrared; PMR, proton magnetic resonance; THF, tetrahydrofuran; ALT, alanine aminotransferase; GC, gas chromatography; MS, mass spectroscopy; TLC, thin-layer chromatography;R f, relative front;R t, retention time; LRMS, low-resolution mass spectra; HRMS, high-resolution mass spectra.
- Received October 16, 2000.
- Accepted February 5, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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