Induction of Quinone Reductase by Withanolides Isolated from Physalis philadelphica (Tomatillos)

Abstract

The fruits of Physalis philadelphica, known commonly as tomatillos, are an ingredient of the condiment “salsa verde”. As part of an ongoing project to discover natural product cancer chemopreventive agents, an ethyl acetate-soluble extract of the commercially available fresh fruits of P. philadelphica was found to induce quinone reductase activity in cultured Hepa 1c1c7 murine hepatoma cells. Bioassay-directed fractionation of an EtOAc extract of the fruits, aided by LC/MS, led to the isolation of a series of structurally related withanolides. One novel substance, 2,3-dihydro-3-methoxywithaphysacarpin (1), and two known compounds, withaphysacarpin (2) and 24,25-dihydrowithanolide D (3), were isolated, with the structure of 1 characterized spectroscopically. All three withanolides significantly induced quinone reductase activity in Hepa 1c1c7, TAPclBPrc1, and BPrcl murine hepatoma cells, suggesting that these compounds are monofunctional inducers, specifically elevating phase II enzymes responsible for detoxification, while not influencing phase I enzymes that may activate carcinogens. Keywords: Physalis philadelphica; Solanaceae; tomatillo; 2,3-dihydro-3-methoxywithaphysacarpin; withaphysacarpin; 24,25-dihydrowithanolide D; withanolides; quinone reductase induction; cancer chemoprevention