Flavonoids as hormones. A perspective from an analysis of molecular fossils

Although for centuries plants have been known to have hormone-like actions in humans, the mechanism(s) by which plant-derived compounds act in humans is still being elucidated, a goal that has assumed more importance due to interest in the protective actions of fruits and vegetables in diseases such as cancer. Here I use the "molecular fossil record" of amino acid sequences of proteins involved in regulating the actions steroids, retinoids, thyroid hormone and prostaglandins to propose some mechanisms by which flavonoids in fruits and vegetables can have hormone-like actions in humans. I focus on: i) hormone receptors that bind to DNA and regulate gene transcription and ii) the enzymes that regulate the concentrations of these hormones. Comparative analyses of amino acid sequences show that nuclear receptors for steroids, retinoids, thyroid hormone and prostaglandins in humans and insects are descended from a common ancestor. Similar analyses of dehydrogenases that regulate the concentrations of steroids, retinoids and prostaglandins reveal strong sequence similarity to enzymes in plants, insects, fungi, and bacteria. The similarity is sufficient to suggest that some compounds that bind receptors or enzymes in invertebrates, plants or unicellular organisms may also bind to mammalian homologs that are involved in endocrine physiology. Among the phytochemicals that are candidates for such activity are flavonoids because they are involved in plant-insect and plant-bacteria interactions and have some structural and chemical similarities to steroids, retinoids, thyroid hormone, prostaglandins and fatty acids. These similarities and the kinship of human, plant, insect and bacterial proteins involved in signal transduction provide a conceptual framework for investigating flavonoids for hormone-like actions in humans. Understanding these modes of action may be useful in developing protocols for preventing hormone-dependent diseases such as breast and prostate cancer.