Cancer Prevention Program

Isothiocyanates as Specific Antagonists of Suman SXR

PI: Johanna Lampe PhD

Adverse drug interactions (ADI) are a major public health problem in the US. A major contributor to both ADI and failure of therapeutic efficacy is genetic variability and/or environmentally-induced (incl. diet) changes in hepatic and intestinal drug disposition. Cytochrome P450 3A4 (CYP3A4) is responsible for the hepatic and intestinal metabolism of numerous xenobiotics, including pharmaceuticals, some carcinogens, and several important endogenous steroids. Constitutive and inducible expression of CYP3A4 is regulated by a variety of different transcription factors/pathways. Among the most important determinants of CYP3A4 activity is the hormone nuclear receptor, Steroid and Xenobiotic Receptor (SXR; also known as the Pregnane X-receptor, PXR). Numerous drugs and non-drug chemicals induce CYP3A4 activity by acting as SXR ligands, and can cause significant adverse drug-drug interactions and alter therapeutic efficacy. In studies initially investigating the chemopreventive actions of the dietary phytochemical, sulforaphane (SFN; an isothiocyanate found in broccoli), we found that SFN causes remarkable 'down-regulation’ of CYP3A4 in human hepatocytes. Additional studies demonstrated that this is a species (human)-specific effect, consistent with known differences in SXR ligands between rodents and humans. In this grant we propose to conduct a human feeding study to determine if SFN in broccoli sprouts lowers basal expression of human CYP3A4 and/or interferes with rifampin-mediated induction of CYP3A4, measured by midazolam clearance. These results may lead to the development of important new therapeutic and dietary approaches that could reduce adverse drug responses. They could also help explain the large inter-individual variability in CYP3A4 expression and activity that has been noted for decades. Finally, they could help to further elucidate the risks and benefits of sulforaphane, a potential dietary phytochemical that has been proposed as a safe ‘nutraceutical’ compound to reduce cancer risk.

This is a randomized cross-over trial of healthy men and women, 20 and 40 years of age, recruited from the community. Those interested will fill-out a screening questionnaire to ascertain eligibility. In this study we use a medication called midazolam. As the body breaks down this drug, we can see different components of it in urine and blood, therefore it is a very good marker as to how effectively the enzymes in the liver are working. Participants go through three 1-week treatment periods. We will test how effective the enzymes are a) with broccoli in the presence of another medication (rifampin), b) with broccoli but without another medication and c) with no broccoli in the presence of another medication.

For more information contact Lisa Levy.