Resveratrol induces catalytic bioscavenger paraoxonase 1 expression and protects against chemical warfare nerve agent toxicity in human cell lines

Abstract

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.

Diet and Paraoxonase 1 Enzymatic Activity in Diabetic Foot Patients from Romania and Belgium: Favorable Association of High Flavonoid Dietary Intake with Arylesterase Activity

“…Polyphenols from pomegranate juice increase the stability of binding of PON1 to HDL, thus preserving its activity [30] . Moreover, recent investigations of human cell lines have revealed upregulation of PON1 expression and increased arylesterase activity in hepatic cells exposed to resveratrol, an ingredient of common red wine [33,34] . Similarly, rats fed quercetin showed upregulation of PON1 hepatic expression and increased paraoxonase activity, which was associated with improved protection against LDL oxidation [35] .…”

Hormonal and Chemical Regulation of Paraoxonases in Mice

“…In addition, alcohol, wine consumption, resveratrol, pitavastatin, and probucol increase Pon1/PON1 expression and activity in rodents and humans (Rao et al, 2003;Ota et al, 2005;Hong et al, 2006;Rajdl et al, 2007;Curtin et al, 2008). In contrast, dietary taurocholate decreased Pon1 expression in mice through the activation of the farnesoid X receptor-Fgf15-Fgfr4 pathway (Gutierrez et al, 2006).…”

A homogeneous cell-based assay for measurement of endogenous paraoxonase 1 activity

“…Specifically, the statins simvastatin, pitavastatin, atorvastatin have all been reported to enhance PON1 gene transcription. Dietary polyphenols, including flavonoids such as quercetin, and resveratrol have been shown to activate PON1 gene transcription via activation of the aryl hydrocarbon receptor (AhR) [22-25]. Recent data has indicated that aspirin can significantly increase PON1 transcription and high doses of aspirin had a significant affect on serum PON1 activity in animal studies [26].…”