HUMAN METABOLISM OF THE EXPERIMENTAL CANCER THERAPEUTIC AGENT D-LIMONENE

d-Limonene has efficacy in preclinical models of breast cancer, causin g > 80% of carcinomas to regress with little host toxicity. We perform ed a pilot study on healthy human volunteers to identify plasma metabo lites of limonene and to assess the toxicity of supradietary quan titl es of d-limonene. Seven subjects ingested 100 mg/kg limonene in a cust ard. Blood was drawn at 0 and 24 h for chemistry-panel analysis and at 0, 4, and 24 h for limonene-metabolite analysis. On-line capillary ga s chromatography/ mass spectrometry (GC/MS) analysis indicated that at least five compounds were present at 4 h that were not present at tim e zero. Two major peaks were identified as the rat limonene metabolite s dihydroperillic acid and perillic acid, and two minor peaks were fou nd to be the respective methyl esters of these acids. A third major pe ak was identified as limonene-1,2-diol. Limonene was a minor component . At a dose of 100 mg/kg, limonene caused no gradable toxicity. Limone ne is metabolized by humans and rats in a similar manner. These observ ations and the high therapeutic ratio of limonene in the chemotherapy of rodent cancers suggest that limonene may be an efficacious chemothe rapeutic agent for human malignancies.