Bioavailability and Disposition of the Bioactive Food Component D-Limonene, and Implications for Breast Cancer Prevention

Abstract

d-Limonene is a monoterpene found in high concentration in citrus peel oil. Evidence from animal models and cell culture indicate that it has strong anti-cancer effects, particularly in mammary cancer models. Chapter 1; "D-LIMONENE: A BIOACTIVE FOOD COMPONENT FROM CITRUS AND EVIDENCE FOR A POTENTIAL ROLE IN BREAST CANCER PREVENTION AND TREATMENT" is a review paper accepted to Oncology Reviews. This review describes the evidence for d-limonene's anti-cancer mechanisms, bioavailability and safety, focusing on relevance to breast cancer prevention. Chapter 2; "ADIPOSE TISSUE ACCUMULATION OF D-LIMONENE WITH THE CONSUMPTION OF A LEMONADE PREPARATION RICH IN D-LIMONENE CONTENT" is published in Nutrition and Cancer journal and describes a phase I clinical trial in which participants consumed 40 oz of high-limonene lemonade daily. This study demonstrated that after 4 weeks of oral consumption of high-limonene lemonade, d-limonene deposits in high levels in adipose tissue. Chapter 3; "A CLINICAL BIOMARKER STUDY OF TOPICALLY APPLIED D-LIMONENE FOR BREAST CANCER PREVENTION" was submitted to Nutrition and Cancer journal. In this phase 0 clinical study, four weeks of a 10% d-limonene formulation resulted in minimal change in NAF and plasma biomarkers or d-limonene levels. Biomarkers in NAF and plasma, however, were significantly differently correlated with BMI and menopausal status, perhaps suggesting effect modifications. Chapter 4: "MOUSE MAMMARY TISSUE DISTRIBUTION OF D-LIMONENE AND PERILLIC ACID FOLLOWING ORAL AND TOPICAL D-LIMONENE ADMINISTRATION," was a study comparing d-limonene and perillic acid disposition after administration of 10% and 20% d-limonene in coconut oil in topical and oral forms to SKH-1 mice. This study demonstrated that d-limonene deposits in high levels in mouse mammary tissue after both oral and topical administration short-term, but is largely cleared after 24 hours in this model. Perillic acid deposits in high levels in adipose after oral administration, and these high concentrations remained after 24 hours. Chapter 5: "IMPLICATIONS AND FUTURE DIRECTIONS" provides a summary of the key findings from these three projects and proposals for future research. The appendices provide results from smaller d-limonene projects, as well as extensions of the body of the dissertation work.