Resveratrol induces catalytic bioscavenger paraoxonase 1 expression and protects against chemical warfare nerve agent toxicity in human cell lines.
Current advances in enzyme bioscavenger prophylactic therapy against chemical warfare nerve agent (CWNA) exposure are moving towards the identification of catalytic bioscavengers that can degrade large doses of organophosphate (OP) nerve agents without self destruction. This is a preferred method compared to therapy with the purified stoichiometric bioscavenger, butyrylcholinesterase, which binds OPs 1:1 and would thus require larger doses for treatment. Paraoxonase-1 (PON-1) is one such catalytic bioscavenger that has been shown to hydrolyze OP insecticides and contribute to detoxification in animals and humans. Here we investigated the effects of a common red wine ingredient, Resveratrol (RSV), to induce the expression of PON-1 in the human hepatic cell line HC04 and evaluated the protection against CWNA simulants. Dose-response curves showed that a concentration of 20 microM RSV was optimal in inducing PON-1 expression in HC04 cells. RSV at 20 microM increased the extracellular PON-1 activity approximately 150% without significantly affecting the cells. Higher doses of RSV were cytotoxic to the cells. Resveratrol also induced PON-1 in the human lung cell line A549. RSV pre-treatment significantly (P = 0.05) protected the hepatic cells against exposure to 2x LD(50) of soman and sarin simulants. However, lung cells were protected against soman simulant exposure but not against sarin simulant exposure following RSV treatment. In conclusion, these studies indicate that dietary inducers, such as RSV, can up-regulate PON-1, a catalytic bioscavenger, which can then hydrolyze and protect against CWNA-induced toxicity, providing a prospective new method to protect against CWNA exposure.
Curtin
Bryan F
BF
Department of Biochemical Pharmacology, Division of Biochemistry, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, Maryland 20910-7500, USA.
Seetharam
Karthik I
KI
Dhoieam
Pilin
P
Gordon
Richard K
RK
Doctor
Bhupendra P
BP
Nambiar
Madhusoodana P
MP
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D043303:Aryldialkylphosphatase / Q000378:metabolism*; D002091:Butyrylcholinesterase / Q000378:metabolism; D002460:Cell Line; D002619:Chemical Warfare Agents / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D051379:Mice; D000077185:Resveratrol; D012524:Sarin / Q000633:toxicity*; D012999:Soman / Q000633:toxicity*; D013267:Stilbenes / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002619:Chemical Warfare Agents; D013267:Stilbenes; D012999:Soman; D012524:Sarin; D002091:Butyrylcholinesterase; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; D000077185:Resveratrol