Metabolism of (R)-(+)-pulegone and (R)-(+)-menthofuran by human liver cytochrome P-450s: evidence for formation of a furan epoxide.
(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 respective Km and Vmax values of 29 microM and 8.4 nmol/min/nmol P-450 for CYP2E1, 94 microM and 2.4 nmol/min/nmol P-450 for CYP1A2, and 31 microM 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 respective Km and Vmax values of 33 microM and 0.43 nmol/min/nmol P-450 for CYP2E1, 57 microM and 0.29 nmol/min/nmol P-450 for CYP1A2, and 62 microM and 0.26 nmol/min/nmol P-450 for CYP2C19.
Khojasteh-Bakht
S C
SC
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, Washington 98195-7610, USA.
Chen
W
W
Koenigs
L L
LL
Peter
R M
RM
Nelson
S D
SD
D000818:Animals; D000081005:Cyclohexane Monoterpenes; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism; D005663:Furans / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008610:Menthol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D039821:Monoterpenes; D009336:Necrosis; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D010103:Oxygen Isotopes; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013729:Terpenes / Q000378:metabolism* / Q000633:toxicity
D000081005:Cyclohexane Monoterpenes; D004852:Epoxy Compounds; D005663:Furans; D007527:Isoenzymes; D039821:Monoterpenes; D010103:Oxygen Isotopes; D013729:Terpenes; D008610:Menthol; C054487:menthofuran; C039648:pulegone; D003577:Cytochrome P-450 Enzyme System; D010100:Oxygen