Potential Adverse Effects of Resveratrol: A Literature Review

Abstract

Due to its health benefits, resveratrol (RE) is one of the most researched natural polyphenols. Resveratrol's health benefits were first highlighted in the early 1990s in the French paradox study, which opened extensive research activity into this compound. Ever since, several pharmacological activities including antioxidant, anti-aging, anti-inflammatory, anti-cancerous, anti-diabetic, cardioprotective, and neuroprotective properties, were attributed to RE. However, results from the available human clinical trials were controversial concerning the protective effects of RE against diseases and their sequelae. The reason for these conflicting findings is varied but differences in the characteristics of the enrolled patients, RE doses used, and duration of RE supplementation were proposed, at least in part, as possible causes. In particular, the optimal RE dosage capable of maximizing its health benefits without raising toxicity issues remains an area of extensive research. In this context, while there is a consistent body of literature on the protective effects of RE against diseases, there are relatively few reports investigating its possible toxicity. Indeed, toxicity and adverse effects were reported following consumption of RE; therefore, extensive future studies on the long-term effects, as well as the in vivo adverse effects, of RE supplementation in humans are needed. Furthermore, data on the interactions of RE when combined with other therapies are still lacking, as well as results related to its absorption and bioavailability in the human body. In this review, we collect and summarize the available literature about RE toxicity and side effects. In this process, we analyze in vitro and in vivo studies that have addressed this stilbenoid. These studies suggest that RE still has an unexplored side. Finally, we discuss the new delivery methods that are being employed to overcome the low bioavailability of RE.

Keywords: anticancer; antioxidant effects; biphasic; oxidative DNA damage; pro-oxidant effects; reactive oxygen species (ROS); resveratrol.

Figure 1

Biphasic hormetic dose-dependent effects of resveratrol (RE). Resveratrol exhibits biphasic dose-dependent effects. At low concentrations, RE acts as an antioxidant which can protect from DNA damage and oxidative stress. On the other hand, at high concentrations, RE acts as a pro-oxidant promoting DNA damage while increasing oxidative stress. Low and high concentrations offer beneficial effects in the prevention of cancer formation (chemo-preventive) and in the treatment of cancer (cytotoxic), respectively.

Figure 2

Metabolism of resveratrol in the liver.

Figure 3

Resveratrol- and copper-induced cytotoxicity. The cytotoxic mechanisms of RE include the mobilization of endogenous copper ions, including chromatin-bound copper. Resveratrol undergoes oxidation in the presence of Cu(II) (which is substantially increased in the malignant cells) to a dimer. This electron transfer reduces Cu(II) to Cu(I). The dimer is capable of binding DNA to form a DNA–RE–Cu(II) ternary complex which allows the efficient cleavage of DNA. Considering that RE and copper-induced DNA damage will be considerably greater in cancer cells, this mechanism offers a way for the selective killing of cancer cells by using high concentrations of RE.

Figure 4

RE can affect all stages of carcinogenesis. RE can attenuate the various stages of cancer development, depending on its concentration. At low to moderate concentrations, RE, by acting as a chemopreventive agent, can block cancer initiation. This is achieved by suppression of spontaneous mutations and a reduction of cancer promotion that can lead to decreased tumor growth rate. At higher concentrations, RE can alter the late stages of carcinogenesis. By acting as a cytotoxic agent, RE can halt the progression and metastasis of cancer cells through the inhibition of angiogenesis and invasion of primary tumor cells. Hence, RE can be used to prevent cancer formation at its early stages or halt the progression and subsequent metastasis by acting as a cytotoxic agent [202,203,204,205,206].