The present study showed that oral administration of tangeretin (TAN) in mice resulted in the production of 4'-demethyltangeretin (4DT) as a major urinary metabolite. The anti-inflammatory efficacy of TAN and 4DT was determined in RAW 264.7 macrophages stimulated by lipopolysaccharides (LPS). 4DT produced considerably stronger inhibition on the overproduction of prostaglandin E2 and nitric oxide than TAN did at the same concentrations. Western blot and quantitative polymerase chain reaction analyses indicated that 4DT exerted more potent suppressive activity on the over-expression of interleukin-1β, inducible nitric oxide synthase, and cyclooxygenase-2 than TAN. Treatments with TAN and 4DT diminished LPS-stimulated nuclear factor κB (NFκB) translocation via suppressing the degradation of inhibitor κB (IκBα). Furthermore, both compounds attenuated mitogen-activated protein kinases (MAPKs) and Akt signaling upregulated by LPS. Overall, our findings showed that TAN and 4DT inhibited the LPS-stimulated inflammatory response in macrophages by suppressing Akt/MAPKs/NFκB proinflammatory pathways, while 4DT showed more potent activity than TAN, its parent compound.
Keywords: 4′-demethyltangeretin; biotransformation; inflammation; metabolite; tangeretin.