Hormetic dietary phytochemicals

Abstract

Compelling evidence from epidemiological studies suggests beneficial roles of dietary phytochemicals in protecting against chronic disorders such as cancer, and inflammatory and cardiovascular diseases. Emerging findings suggest that several dietary phytochemicals also benefit the nervous system and, when consumed regularly, may reduce the risk of disorders such as Alzheimer's and Parkinson's diseases. The evidence supporting health benefits of vegetables and fruits provide a rationale for identification of the specific phytochemicals responsible, and for investigation of their molecular and cellular mechanisms of action. One general mechanism of action of phytochemicals that is emerging from recent studies is that they activate adaptive cellular stress response pathways. From an evolutionary perspective, the noxious properties of such phytochemicals play an important role in dissuading insects and other pests from eating the plants. However at the subtoxic doses ingested by humans that consume the plants, the phytochemicals induce mild cellular stress responses. This phenomenon has been widely observed in biology and medicine, and has been described as 'preconditioning' or 'hormesis.' Hormetic pathways activated by phytochemicals may involve kinases and transcription factors that induce the expression of genes that encode antioxidant enzymes, protein chaperones, phase-2 enzymes, neurotrophic factors, and other cytoprotective proteins. Specific examples of such pathways include the sirtuin-FOXO pathway, the NF-kappaB pathway, and the Nrf-2/ARE pathway. In this article, we describe the hormesis hypothesis of phytochemical actions with a focus on the Nrf2/ARE signaling pathway as a prototypical example of a neuroprotective mechanism of action of specific dietary phytochemicals.

Figure 1

The concept and biphasic dose-response characteristic of hormesis. Hormesis can be initiated by exposure to various environmental stressors including ingestion of phytochemicals. Such exposures typically result in mild cellular stress involving free radical production, ion fluxes and increased energy demand. As a result, adaptive stress response pathways are activated leading to the synthesis of proteins that protect cells against more severe stress. Examples of stress resistance proteins include antioxidants, protein chaperones, growth factors, and proteins involved in the regulation of energy metabolism and cellular calcium homeostasis.

Figure 2

Detoxification pathways. Potentially noxious chemicals ingested with food undergo enzymatic metabolism in a coordinated process involving phase I, II and III enzymes; metabolites are then excreted from the body. Some such phytochemicals induce the expression of phase II enzymes via the Nrf2/ARE pathway.

Figure 3

Model of activation of Nrf2-mediated ARE pathway by phytochemicals. Phytochemicals may act directly on the Nrf2-Keap1 complex, or alternatively on upstream kinases such as PI3K, p38, ERK, PKC, JNK, causing the release of Nrf2 from the inhibitory complex. Additionally, certain phytochemicals may act at the level of the proteasome to inhibit proteolytic degradation of Nrf2 and prolong its half-life. Activated Nrf2 translocates into the nucleus where it interacts with small MAF family proteins bound to the antioxidant response element (ARE), allowing transcription of target genes including those including antioxidant and phase II enzymes.