Submitted to: Biomed Central (BMC) Pharmacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/13/2008
Publication Date: 8/13/2008
Publication URL: http://www.biomedcentral.com/1471-2210/8/15
Citation: Wilson, M.A., Rimando, A.M., Wolkow, C.A. 2008. Methoxylation Enhances Stilbene Bioactivity in Caenorhabditis elegans. Biomed Central (BMC) Pharmacology. 8:15. Interpretive Summary: Stilbenes are compounds produced by plants in response to stress, which also exhibit other biological activities such as inhibition of cancer cell growth, neuroprotection, and immune modulation. Stilbenes that have hydroxyl groups are metabolized and excreted faster than those with methoxy groups. In this study, we compared the activities of these compounds using roundworms. The stilbenes having methoxy groups, but not those with hydroxyl groups, were found to be toxic to the roundworms and also exhibited stronger inhibition of tumor growth in the worms. Increasing number of methoxy groups was associated with a greater degree of toxicity. These findings demonstrate that stilbene methoxylation increases bioactivity in a whole organism. Differences in bioactivity in adult worms did not appear to correlate with differential uptake. The potent activities of methoxylated stilbenes provide a basis for further investigations to identify in vivo targets for these compounds.
Technical Abstract: Background. Stilbenes are 1,2-diphenylethylene congeners produced by plants in response to stress. Many stilbenes also exhibit xenobiotic activities in animal cells, such as inhibition of cancer cell growth, neuroprotection, and immune modulation. In vivo, hydroxylated stilbenes are metabolized by glucuronidation to facilitate excretion. Methoxylated stilbenes are metabolized more slowly, which may have a positive effect on in vivo bioactivity. Here, we have directly compared in vivo bioactivities of methoxylated and hydroxylated stilbenes in a whole organism using the roundworm Caenorhabditis elegans, which has a rapid lifecycle and can be maintained economically in the laboratory. Results. Toxicity towards C. elegans adults was observed for methoxylated stilbenes, but not for hydroxylated stilbenes. Increasing methoxylation was associated with a greater degree of toxicity. Methoxylated stilbenes also exhibited stronger inhibitory effects than hydroxylated stilbenes on germline tumor growth in gld-1(q485) adults. However, steady-state levels of three methoxylated stilbenes did not directly correlate to their relative bioactivities. Conclusions. These findings demonstrate that stilbene methoxylation can increase bioactivity in vivo in a whole organism. Differences in bioactivity in C. elegans adults did not appear to correlate with differential uptake. Rather, we speculate that methoxylated stilbenes may have increased interactions with biological targets in vivo or may interact with specific targets unaffected by hydroxylated stilbenes. The potent activities of methoxylated stilbenes provide a basis for further investigations to identify in vivo targets for these compounds.