Abstract
(R)-(+)-Pulegone, a monoterpene constituent of pennyroyal oil, is a hepatotoxin that has been used in folklore medicine as an abortifacient despite its potential lethal effects. Pulegone is metabolized by human liver cytochrome P-450s to menthofuran, a proximate hepatotoxic metabolite of pulegone. Expressed human liver cytochrome (CYP) P-450s (1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4) were tested for their ability to catalyze the oxidations of pulegone and menthofuran. Expressed CYP2E1, CYP1A2, and CYP2C19 oxidized pulegone to menthofuran, with respectiveKm and Vmaxvalues of 29 μM and 8.4 nmol/min/nmol P-450 for CYP2E1, 94 μM and 2.4 nmol/min/nmol P-450 for CYP1A2, and 31 μM and 1.5 nmol/min/nmol P-450 for CYP2C19. The human liver P-450s involved in the metabolism of menthofuran are the same as pulegone except for the addition of CYP2A6. These P-450s were found to oxidize menthofuran to a newly identified metabolite, 2-hydroxymenthofuran, which is an intermediate in the formation of the known metabolites mintlactone and isomintlactone. Based on studies with 18O2 and H218O, 2-hydroxymenthofuran arises predominantly from a dihydrodiol formed from a furan epoxide. CYP2E1, CYP1A2, and CYP2C19 oxidized menthofuran with respectiveKm andVmax values of 33 μM and 0.43 nmol/min/nmol P-450 for CYP2E1, 57 μM and 0.29 nmol/min/nmol P-450 for CYP1A2, and 62 μM and 0.26 nmol/min/nmol P-450 for CYP2C19.
Footnotes
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Send reprint requests to: Sidney D. Nelson, Ph.D., Medicinal Chemistry, University of Washington, Box 357610, Seattle, WA 98195-7610. E-mail: sidnels{at}u.washington.edu
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This work was supported by National Institutes of Health Grants GM 25418 and GM 32165 (to S.D.N.).
- Abbreviations used are::
- DDC
- diethyldithiocarbamate
- DLPC
- dilauryl-dl-α-phosphatidylcholine
- dimethoxymenthofuran
- α,α′-dimethoxydihydromenthofuran
- HL
- human liver microsomes
- 2-hydroxymenthofuran
- (R)-2-hydroxymenthofuran
- isomintlactone
- (+)-isomintlactone
- menthofuran
- (R)-(+)-menthofuran
- mintlactone
- (−)-mintlactone
- P-450
- human liver cytochrome P-450
- pulegone
- (R)-(+)-pulegone
- r
- correlation coefficient
- TDC
- 5,6,7,8-tetrahydro-4,7-dimethyl-7H-cinnoline
- Received November 9, 1998.
- Accepted January 29, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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Metabolism of (R)-(+)-Pulegone and (R)-(+)-Menthofuran by Human Liver Cytochrome P-450s: Evidence for Formation of a Furan Epoxide
