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.
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)-cyclo hexano ne (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 microM. 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.
Thulasiram
H V
HV
Bio-organic Section, Department of Organic Chemistry, Indian Institute of Science, Bangalore, India.
Gadad
A K
AK
Madyastha
M K
MK
D000633:Aminopyrine N-Demethylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D002251:Carbon Tetrachloride / Q000494:pharmacology; D000081005:Cyclohexane Monoterpenes; D003512:Cyclohexanones / Q000493:pharmacokinetics* / Q000633:toxicity; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005952:Glucose-6-Phosphatase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008099:Liver / Q000187:drug effects*; D008297:Male; D008610:Menthol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D039821:Monoterpenes; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
C411873:5,5-dimethyl-2-(1-methylethylidene)cyclohexanone; D000081005:Cyclohexane Monoterpenes; D003512:Cyclohexanones; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D039821:Monoterpenes; D008610:Menthol; C039648:pulegone; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; D000633:Aminopyrine N-Demethylase; D005952:Glucose-6-Phosphatase