Inhibition of protein prenylation by metabolites of limonene

Biochem Pharmacol. 1999 Apr 1;57(7):801-9. doi: 10.1016/s0006-2952(98)00349-9.

Abstract

The monoterpenes limonene and perillyl alcohol are undergoing clinical evaluation in cancer patients. In this paper, we report the chemical synthesis, characterisation, and quantitation in patients' plasma of a novel human metabolite of limonene, which is identified as an isomer of perillic acid. The synthesis of R-perillic acid is also described, because previous reports on the activity of perillic acid against isoprenylation enzymes refer to the S-enantiomer, although it is the R-enantiomer which is the metabolite of R-limonene. The above monoterpenes, with several related compounds, were assayed for inhibitory activity towards the isoprenylation enzymes in rat brain cytosol. Although R- and S-limonene are only weak inhibitors of the isoprenylation enzymes, their major metabolites, perillic acid and perillyl alcohol, 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 displays IC50 values similar to those of perillic acid suggesting that it may contribute to the in vivo activity of limonene.

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors
  • Animals
  • Antineoplastic Agents, Phytogenic / blood
  • Antineoplastic Agents, Phytogenic / metabolism*
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Brain / drug effects
  • Brain / metabolism
  • Chromatography, High Pressure Liquid
  • Cyclohexane Monoterpenes
  • Cyclohexenes
  • Cytosol / drug effects
  • Cytosol / metabolism
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Farnesyltranstransferase
  • Humans
  • In Vitro Techniques
  • Limonene
  • Mass Spectrometry
  • Monoterpenes*
  • Nerve Tissue Proteins / metabolism
  • Protein Prenylation / drug effects*
  • Rats
  • Terpenes / blood
  • Terpenes / metabolism*
  • Terpenes / pharmacology*

Substances

  • Antineoplastic Agents, Phytogenic
  • Cyclohexane Monoterpenes
  • Cyclohexenes
  • Enzyme Inhibitors
  • Monoterpenes
  • Nerve Tissue Proteins
  • Terpenes
  • carvone
  • perillic acid
  • Limonene
  • Alkyl and Aryl Transferases
  • geranylgeranyltransferase type-I
  • Farnesyltranstransferase