Inhibition of protein prenylation by metabolites of limonene

The monoterpenes limonene and perillyl alcohol are undergoing clinical eval uation in cancer patients. In this paper, we report the chemical synthesis, characterisation, and quantitation in patients' plasma of a novel human me tabolite of limonene, which is identified as an isomer of perillic acid. Th e synthesis of R-perillic acid is also described, because previous reports on the activity of perillic acid against isoprenylation enzymes refer to th e S-enantiomer, although it is the R-enantiomer which is the metabolite of R-limonene. The above monoterpenes, with several related compounds, were as sayed for inhibitory activity towards the isoprenylation enzymes in rat bra in cytosol. Although R- and S-limonene are only weak inhibitors of the isop renylation enzymes, their major metabolites, perillic acid and perillyl alc ohol, are more potent inhibitors, with IC50 values in the low mM range. The metabolites possess greater activity towards the geranylgeranyltransferase type I enzyme than farnesyltransferase, while the novel metabolite display s IC50 values similar to those of perillic acid suggesting that it may cont ribute to the in vivo activity of limonene. (C) 1999 Elsevier Science Inc.