Cytotoxicity and biotransformation of the anticancer drug perillyl alcoholin PC12 cells and in the rat

The cytotoxic monoterpene perillyl alcohol (POH) has anticancer properties. We investigated its cytotoxicity in PC12 cells in relation to its biotrans formation. POH is oxidized by alcohol dehydrogenase and aldehyde dehydrogen ase to perillaldehyde (PCO) and perillic acid (PCOOH), respectively. Apopto sis was determined by cell cycle (subG(0)G(1)) analysis and AnfiexinV stain ing followed by flow cytometry. PCO caused apoptosis at 200 mu M, POH cause d apoptosis from 500 PM on, while PCOOH had no effect. The caspase inhibito r zVAD prevented apoptosis. Inhibition of POH oxidation by 4-methylpyrazol did not prevent the apoptotic effect of POH indicating that POH itself is a lso apoptotic. To find out to what extent POH is metabolized to PCO, the me tabolism of POH, PCO, and PCOOH was determined after intravenous injection in the rat and in isolated hepatocytes. Although PCO can form a glutathione conjugate(s), no indication of the formation of GSH conjugates was found e ither in vivo or in hepatocytes. About 70% of the dose was recovered as glu curonides in bile and urine. PCOOH generated only the acyl glucuronide, whi le POH and PCO formed both acyl and ether glucuronides, These results indic ate that PCO is a major intermediary metabolite of POH in the rat in,vivo a nd suggest that PCO may contribute to the anticancer effect of POH. (C) 200 0 Academic Press.