Limonene is a lipophilic
monoterpene found in high levels in citrus peel.
Limonene demonstrates anticancer properties in preclinical models with effects on multiple cellular targets at varying potency. While of interest as a
cancer chemopreventive, the
biologic activity of
limonene in humans is poorly understood. We conducted metabolite profiling in 39 paired (pre/postintervention) plasma samples from early-stage
breast cancer patients receiving
limonene treatment (2 g QD) before surgical resection of their
tumor. Metabolite profiling was conducted using ultra-performance liquid chromatography coupled to a linear trap quadrupole system and gas chromatography-mass spectrometry. Metabolites were identified by comparison of ion features in samples to a standard reference library. Pathway-based interpretation was conducted using the human metabolome database and the MetaCyc database. Of the 397 named metabolites identified, 72 changed significantly with
limonene intervention. Class-based changes included significant decreases in adrenal
steroids (P < 0.01), and significant increases in
bile acids (P ≤ 0.05) and multiple
collagen breakdown products (P < 0.001). The pattern of changes also suggested alterations in
glucose metabolism. There were 47 metabolites whose change with intervention was significantly correlated to a decrease in
cyclin D1, a cell-cycle regulatory
protein, in patient
tumor tissues (P ≤ 0.05). Here,
oral administration of
limonene resulted in significant changes in several metabolic pathways. Furthermore, pathway-based changes were related to the change in tissue level
cyclin D1 expression. Future controlled clinical trials with
limonene are necessary to determine the potential role and mechanisms of
limonene in the
breast cancer prevention setting.