An anti-inflammatory role for bioactive nutrient isothiocyanates

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DESCRIPTION (provided by applicant): Fresh fruits and vegetables are the foundation of a healthy diet. They not only provide vitamins and minerals that are essential for human health, but they also contain bioactive nutrients that have demonstrated efficacy in preventing cancer in animal models. While this phenomenon of cancer chemoprevention is well appreciated, the mechanism by which these bioactive nutrients bring about these effects remains obscure. Moreover, the possibility of other, more subtle health benefits arising from these bioactive nutrients has been mostly ignored. One class of chemopreventive compounds, the bioactive nutrient isothiocyanates (ITCs), are abundant in cruciferous vegetables such as broccoli, and have a chemical structure that suggest that they could covalently react with proteins in the cell. In an effort to further understand the mechanism of action of these chemicals, we undertook a screen to isolate protein targets of bioactive nutrient ITC modification. We isolated a predominant target of this class of bioactive nutrients that is a critical mediator of inflammatory disease processes. Modification by nutritional ITCs inhibits the enzymatic activity of this protein, suggesting bioactive nutrient ITCs may inhibit the downstream functions of the protein that drive inflammation. We propose that the degree of bioactive nutrient ITC modification of this protein may represent a valuable surrogate biomarker of effective delivery. Modification of this protein represents a measure of bioavailability that can be applied not only to biological fluids, but also to potential target tissues. We present experiments designed to develop this biomarker as a means to examine the bioavailability and trace the pharmacokinetics and pharmacodynamics of bioactive nutrient ITCs in an intact animal. In addition, we propose that the bioactive nutrient ITCs may have previously unappreciated anti-inflammatory benefits as a result of their ability to modify and inhibit this critical mediator of inflammation. We will examine this possibility using a classical model of inflammation in combination with animals deficient in this protein target. These studies will allow us to both probe the potential anti-inflammatory properties of bioactive nutrient ITCs, as well as define a potential molecular mechanism for their effectiveness.