In search of a mechanism: food polyphenols from antioxidants to modulators of gene expression

IN SEARCH OF A MECHANISM: FOOD POLYPHENOLS FROM ANTIOXIDANTS TO MODULATORS OF GENE EXPRESSION Piero Dolara, Cristina Luceri, Elisabetta Bigagli, Vanessa Pitozzi, Lisa Giovannelli, Department of Preclinical and Clinical Pharmacology, University of Florence, Italy Email: piero.dolara@unifi.it Food is an important determinant of cancer. A high intake of fruit and vegetables has been linked to a decreased incidence of human tumours. Since most plant materials contain polyphenols, the possibility was suggested that plant polyphenols might have a cancer-preventive activity. Polyphenols from tea and grapes have shown cancer-inhibiting activity in experimental animal models; however, the mechanism through which food polyphenols modulate cancer risk were unknown or speculative. We carried out experiments in rodents to study the effect of plant materials containing polyphenols on the gene regulation of the colon mucosa and liver, which come into contact with polyphenols or their metabolites (mutant strains of Arabidopsis Thaliana, varieties of apples and strawberries containing various amounts of phenolic acids and complex polyphenols, polyphenol-rich and depleted olive oil). No major changes in DNA oxidative damage were found in the organs studied, except in animals treated with flavonol-rich Arabidopsis seeds. Gene expression profiles were investigated in liver and colon mucosa samples using rat oligonucleotide arrays, (Rat Genome Oligo Set Version 1.1™ , Operon Technologies, CA, USA) and composed of 5,677 oligonucleotides (70mers), each representing one gene. We compared the gene expression profile of animals fed high polyphenol diets vs reference pools obtained by RNA extracts from rodents fed the same diets devoid or with low levels of polyphenols. GenMAPP and MAPPFinder analysis revealed effects of polyphenols on genes regulating cell growth, transport, regulation of transcription, metabolism, apoptosis, inflammatory and defense responses. The combination of gene-regulatory effects were variable with different polyphenol-containing foods. Some of the foods containing high phenolic acids (Marie Ménard apples) had a marked anti-inflammatory effect. We propose that the change in gene regulation induced by polyphenol-containing foods, associated with variation of intestinal flora, might explain their cancer- modulating activity in vivo. Some of the anti-inflammatory phenolic acids present in foods may have cancer-preventive properties on their own.