The alpha-methylene-gamma-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.
Inducible heme oxygenase (HO)-1 acts against oxidants that are thought to play a major role in the pathogenesis of several diseases. The alpha-methylene-gamma-butyrolactone (CH2-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 CH2-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 CH2-BL, a parent structure of dehydrocostus lactone. In contrast, mokko lactone, a reduced product of dehydrocostus lactone, and alpha-methyl-gamma-butyrolactone (CH3-BL), a parent structure of mokko lactone, did not induce HO-1 expression. Pretreatment with either dehydrocostus lactone or CH2-BL for 6 h protected the cells from hydrogen peroxide-mediated toxicity, whereas mokko lactone or CH3-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 CH2-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 CH2-BL. Collectively, our findings suggest that CH2-BL moiety in dehydrocostus lactone increases cellular resistance to oxidant injury in HepG2 cells, presumably through Nrf2/ARE-dependent HO-1 expression.
Jeong
Gil-Saeng
GS
Medicinal Resources Research Institute, Wonkwang University, Iksan, Chonbug 570-749, Republic of Korea.
Pae
Hyun-Ock
HO
Jeong
Sun-Oh
SO
Kim
Youn-Chul
YC
Kwon
Tae-Oh
TO
Lee
Ho Sub
HS
Kim
Nam-Song
NS
Park
Seok Don
SD
Chung
Hun-Taeg
HT
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D021581:Active Transport, Cell Nucleus; D000975:Antioxidants / Q000494:pharmacology*; D002460:Cell Line; D019610:Cytoprotection; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D020218:Response Elements / Q000502:physiology; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*
D000975:Antioxidants; D007783:Lactones; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012717:Sesquiterpenes; C097581:mokko lactone; C014096:alpha-methylene gamma-butyrolactone; C083030:dehydrocostus lactone; D051547:Heme Oxygenase-1; D015107:4-Butyrolactone