Hepatoprotective effects and structure-activity relationship of five flavonoids against lipopolysaccharide/d-galactosamine induced acute liver failure in mice

Acute liver failure (ALF) is a distinct clinical syndrome with high mortality and characterized by metabolic derangements, neurological complication , and multiple failures. Flavonoids exert great biological properties on anti-oxidation, anti-inflammation, and anti-apoptosis. After lipopolysaccharide (LPS)/ d -galactosamine ( d -GalN) administration, five flavonoids inhibited oxidative activities with reducing nitric oxide synthase (iNOS), malondialdehyde (MDA), and improving catalase (CAT), superoxide dismutase (SOD), total antioxidant capacity (T-AOC), nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). They reduced the serum levels of alanine and aspartate aminotransferase (ALT, AST) and pro-inflammatory cytokines, prevented the phosphorylation of IKK, IκBα, and NF-κB/p65 in the NF-κB signaling pathway . Additionally five flavonoids inhibited hepatocyte apoptosis through increasing Bcl-2/Bax ratio and suppressing the Caspase family proteins. Chrysin , luteolin , apigenin , hesperetin and 3′, 4′-dimethoxy hesperetin have apparently hepato-protective effects against ALF induced by LPS/ d -GalN. The study found, the C2 C3 double bond at A ring, and the hydroxyl group of C3′ or C4′ at B ring increased the protective activities, however, the effect of hydroxymethylation at C3′ and C4′ was reversed. In addition, apigenin has good hepatoprotective effects and potential as a promising therapeutic agent for ALF in clinical application.