Stereoselective metabolism of the monoterpene carvone by rat and human liver microsomes

The large amounts of carvone enantiomers consumed as food additives and in dental formulations justifies the evaluation of their biotransformation pat hway. The in-vitro metabolism of R-(-)- and S-(+)-carvone was studied in ra t and human liver microsomes using chiral gas chromatography. Stereoselective biotransformation was observed when each enantiomer was inc ubated separately with liver microsomes. 4R, 6S-(-)-Carveol was NADPH-depen dently formed from R-(-)-carvone, whereas 4S, 6S-(+)-carveol was produced f rom S-(+)-carvone. Metabolite formation followed Michaelis-Menten kinetics exhibiting a significant lower apparent K-m (Michaelis-Menten Constant) for 4R, 6S-(-)-carveol compared with 4S, 6S-(+)-carveol in rat and human liver microsomes (28.4 +/- 10.6 mu M and 69.4 +/- 10.3 mu M vs 33.6 +/- 8.5 mu M and 98.3 +/- 22.4 mu M). The maximal formation rate (V-max) determined in the same microsomal preparations yielded 30.2 +/- 5.0 and 32.3 +/- 3.9 pmol (mg protein)(-1) min(-1) in rat liver and 55.3 +/- 5.7 and 65.2 +/- 4.3 pm ol (mg protein)(-1) min(-1) in human liver microsomes. Phase II conjugation of the carveol isomers by rat and human liver microsomes in the presence o f UDPGA (uridine S'-diphosphogluaronic acid) only revealed glucuronidation of 4R, 6S-(-)-carveol. V-max for glucuronide formation was more than 4-fold higher in the rat liver compared with human liver preparations (185.9 +/- 34.5 and 42.6 +/- 7.1 pmol (mg protein)(-1) min(-1), respectively). K-m val ues, however, showed no species-related difference (13.9 +/- 4.1 mu M and 1 0.2 +/- 2.2 mu M) This study demonstrated stereoselectivity in phase-I and phase-II metabolis m for R-(-)- and S-(+)-carvone and might be predictive for carvone biotrans formation in man.