# Resveratrol: A Review on the Biological Activity and Applications
## 15 Risks and Interactions of Resveratrol  
RSV is widely acknowledged for its chemopreentive and antioxidant properties, yet recent studies underscore its potential as a pro-oxidant agent, capable of paradoxically contributing to disease pathology. Although renowned for its ROS-scavenging activity, RSV can also generate ROS, leading to oxidative stress. This biphasic nature manifests in distinct ways depending on dosage and exposure time. At low concentrations (0.1-1.0 ug/mL), it enhances cell proliferation, whereas at higher concentrations (10.0-100.0 ug/mL), it induces apoptosis and reduces mitotic activity in tumor and endothelial cells. Such dose-dependent effects are further influenced by the time of administration, as it behaves as an antioxidant during the dark phase but switches to a pro-oxidant during light periods, indicating a complex interplay between RSV's pro- and antioxidant activities. Additionally, RSV's regulation of mitochondrial function can induce oxidative stress in aged organisms due to a compromised antioxidant defense system, thereby increasing the production of superoxide radicals. Furthermore, its phytoestrogenic properties allow it to act as an agonist or antagonist to ERs, potentially disrupting hormone signaling pathways in certain cancer cell lines. Notably, in aging mice on high-protein diets, RSV was found to exacerbate cardiovascular risk factors by promoting inflammation and superoxide production while decreasing aortic flexibility. These findings emphasize that while RSV offers health benefits, its dose-dependent, dualistic nature necessitates careful consideration to mitigate potential adverse effects [254; 255]. RSV, a promising compound due to its generally non-toxic profile, requires careful dosing to maximize benefits while minimizing adverse effects. While inducing apoptosis in tumor tissues with relatively minimal impact on adjacent healthy cells, higher doses exceeding 2.5 g/day can cause gastrointestinal disturbances like nausea, diarrhea, and vomiting, as well as liver dysfunction, particularly in patients with NAFLD. Notably, RSV remains safe at doses up to 5 g/day over multiple days in healthy individuals. However, challenges arise in understanding its effects due to the metabolism of RSV by gut microbiota [254; 255]. Studies involving animal models highlight the risks of RSV at very high doses. In hypercholesterolemia rabbits, RSV (1 mg/kg) surprisingly promoted atherosclerosis rather than protecting against it. In rats, high doses (3000 mg/kg) led to nephrotoxicity, resulting in elevated blood urea nitrogen and creatinine levels, renal lesions, and renal tubule dilation. High doses also resulted in anemia, weight loss, and elevated liver enzymes, indicating potential liver toxicity [254]. RSV has biphasic effects, meaning that while it can inhibit tumor growth, it also reduces cell growth and induces apoptosis in normal cells at higher concentrations. Doses of 1800 mg/kg reduced the lifespan of mice to 3-4 months. Although it is generally well-tolerated, diarrhea was frequently reported in PK studies with 2000 mg doses administered twice daily. This emphasizes the importance of identifying optimal dosing and administration routes for safe and effective use [254]. RSV's interactions with various medications, particularly through modulation of cytochrome P450 (CYP) enzymes and transporters, highlight the importance of caution in its supplemental use. It inhibits CYP3A4, potentially reducing the metabolic clearance of drugs that rely on this enzyme, leading to elevated bioavailability and increased toxicity. Patients on drugs like tamoxifen, which depend on CYP enzymes for efficacy, could be significantly impacted by high doses of RSV [254; 255]. Moreover, RSV interferes with key transport proteins, including P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2), and organic anion transporter 1/3 (OAT1/OAT3).