The α-methylene-γ-butyrolactone moiety in dehydrocostus lactone is responsible for cytoprotective heme oxygenase-1 expression through activation of the nuclear factor E2-related factor 2 in HepG2 cells

• Published in: European journal of pharmacology 2007-06, Vol.565 (1), p.37-44
• Main Authors: Jeong, Gil-Saeng, Pae, Hyun-Ock, Jeong, Sun-Oh, Kim, Youn-Chul, Kwon, Tae-Oh, Lee, Ho Sub, Kim, Nam-Song, Park, Seok Don, Chung, Hun-Taeg
• Format: Article
• Language: English
• Subjects: 4-Butyrolactone - analogs & derivatives; 4-Butyrolactone - pharmacology; Active Transport, Cell Nucleus; Antioxidant response element; Antioxidants - pharmacology; Biological and medical sciences; Cell Line; Cytoprotection; Dehydrocostus lactone; Heme oxygenase-1; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - physiology; Humans; Lactones - chemistry; Lactones - pharmacology; Medical sciences; NF-E2-Related Factor 2 - physiology; Nuclear factor E2-related factor 2; Pharmacology. Drug treatments; Protection; Response Elements - physiology; Saussurea lappa; Sesquiterpenes - chemistry; Sesquiterpenes - pharmacology; α-Methylene-γ-butyrolactone
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2007.02.053

Inducible heme oxygenase (HO)-1 acts against oxidants that are thought to play a major role in the pathogenesis of several diseases. The α-methylene-γ-butyrolactone (CH 2-BL) structural unit, which characterizes a group of naturally occurring sesquiterpene lactones, is known to possess numerous biological activities. In the present study, we evaluated dehydrocostus lactone possessing CH 2-BL moiety, one of the bioactive constituents of the medicinal plant Saussurea lappa, as an inducer of cytoprotective HO-1. In HepG2 cells, treatment with dehydrocostus lactone induced HO-1 expression and increased HO activity in a concentration-dependent manner. Similar results were also observed when the cells were incubated with CH 2-BL, a parent structure of dehydrocostus lactone. In contrast, mokko lactone, a reduced product of dehydrocostus lactone, and α-methyl-γ-butyrolactone (CH 3-BL), a parent structure of mokko lactone, did not induce HO-1 expression. Pretreatment with either dehydrocostus lactone or CH 2-BL for 6 h protected the cells from hydrogen peroxide-mediated toxicity, whereas mokko lactone or CH 3-BL failed to exert a cytoprotective action. Inhibition of HO-1 expression by HO-1 small interfering RNA (siRNA) abrogated cellular protection afforded by dehydrocostus lactone or CH 2-BL. In addition, dehydrocostus lactone caused the nuclear accumulation of the nuclear factor E2-related factor 2 (Nrf2) and increased the promoter activity of antioxidant response element (ARE). Using Nrf2 siRNA, Nrf2 activation was confirmed to contribute to cytoprotective HO-1 expression by dehydrocostus lactone or CH 2-BL. Collectively, our findings suggest that CH 2-BL moiety in dehydrocostus lactone increases cellular resistance to oxidant injury in HepG2 cells, presumably through Nrf2/ARE-dependent HO-1 expression.