New application of the commercial sweetener rebaudioside a as a hepatoprotective candidate: Induction of the Nrf2 signaling pathway.

A large population of drug candidates have failed "from bench to bed" due to unwanted toxicities. We intend to develop an alternative approach for drug discovery, that is, to seek candidates from "safe" compounds. Rebaudioside A (Reb-A) is an approved commercial sweetener from Stevia rebaudiana Bertoni. We found that Reb-A protects against carbon tetrachloride (CCl4)-induced oxidative injury in human liver hepatocellular carcinoma (HepG2) cells. Reb-A showed antioxidant activity on reducing cellular reactive oxygen species and malondialdehyde levels while increasing glutathione levels and superoxide dismutase and catalase activities. Reb-A treatment induced nuclear factor erythroid-derived 2-like 2 (Nrf2) activation and antioxidant response element activity, as well as the expression of heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). Further mechanistic studies indicated that c-Jun N-terminal kinase (JNK), extracellular signal-regulated protein kinase (ERK), mitogen-active protein kinase (MAPK) and protein kinase C epsilon (PKCε) signaling was upregulated. Thus, the present in vitro study conclusively demonstrated that Reb-A is an activator of Nrf2 and is a potential candidate hepatoprotective agent. More importantly, the present study illustrated that seeking drug candidates from "safe" compounds is a promising strategy.