Mediterranean diet, citrus peels as a source of bioavailable dietary d-limonene:
phase I clinical trials
Prevention is now viewed as the foundation upon which new cancer management strategies should be built. During the last 30 years, research in the field of nutrition and cancer causation has led to exciting, significant progress in providing an understanding of specific risk factors and identifying potential agents in the diet.
Non-nutrient compounds in the diet belonging to different categories of chemicals have been found to exert inhibitory effects in experimental carcinogenesis. D-Limonene, which comprises >90% of citrus peel oil, is of significant interest because it has the capacity to inhibit the carcinogenesis processes via a variety of mechanisms. Chemotherapeutic activities of pharmaceutical preparations of d-limonene can vary considerably depending on the types of citrus consumed and the preparation and processing procedures.
We have developed a preliminary d-limonene database and documented that fresh limonade prepared with the whole lemon (Mediterranean-style lemonade) contains higher levels of d-limonene compared to other citrus products. We have conducted a phase I pharmacokinetic study to determine the systemic availability of perillic acid, a major and biologically active metabolite of d-limonene, following a single dose administration of Mediterranean-style lemonade. This study illustrated that the major metabolite of d-limonene is bioavailable following oral consumption of a citrus preparation rich in d-limonene content.
Subsequently, we conducted a phase I, randomized, chronic feeding trial to assess the long-term safety and sustainability of high limonene consumption, and to determine the systemic bioavailability of d-limonene, following 4-weeks of daily consumption of 40 oz of either commercial orange juice or Mediterranean-style lemonade.
Twenty-two healthy volunteers were randomly assigned to drink 40 oz of lemonade (n=12) or orange juice (n=10) per day for 4 weeks. At baseline, perillic acid was not detected in fasting plasma. Two hours after drinking lemonade, plasma perillic acid concentrations ranged from 0.10 to 0.50 μg/ml (1.20 μM). The 2-hour post ingestion levels of plasma perillic acid were significantly lower (p<0.001) among orange juice consumers and ranged from 0 to 0.08 μg/ml (0 to 0.51 μM), with an average concentration of 0.03 μg/ml (0.15 μM). A similar pattern was seen at the end of the 4-week feeding period (p<0.001).
Furthermore, after 4 weeks of intervention, perillic acid was only detected in the fasting plasma from lemonade drinkers. One month of daily drinking of either citrus product has been shown to be safe with no treatment related adverse effects.
Evaluating the safety and acceptability of chronic high dietary limonene intake in healthy populations is important in order to devise a safe and feasible dietary intervention approach to increase d-limonene exposure.
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