Hepatoprotective Activity And Structure-activity Relationship Of Auriculatone

Objective: To understand the hepatoprotective activity and structure-activity relationship of auriculatone. Methods: The hepatoprotective activity effect was evaluated by testing the cell viability as well as the leakage of alanine transaminase(ALT), aspartate transaminase(AST), and glutathione(GSH) on the APAP-induced HL-7702 normal hepatic cell injury model; oxidative decarboxylation of echinocystic acid gave auriculatone and its 17-epimer. Structural modification of auriculatone at the 3-OH, 16-CO-, or ?12 afforded a series of derivatives. Structure-activity relationship was discussed on the basis of the hepatoprotective activity of auriculatone and its derivatives. Based on the possible mechanism indicated in the activity, the potential targets of auriculatone was revealed by using the computer-aided molecular docking method. The target and structure-activity relationship were further analyzed by the docking experiments of all the auriculatone derivatives. Results: Activity evaluation shows that, auriculatone and its 17-H epimer significantly increased the cell viability and reduce the cellular leakage of ALT and AST induced by APAP at 0.1, 1, and 10 μmol/L, with potency close to that of NAC at 10 μmol/L(P>0.5). However, different from NAC, auriculatone had no effect on the cellular GSH, which suggested a different mechanism of action for its protective effect against APAP cytotoxicity. A total of eight auriculatone derivatives were synthesized. Structure-activity relationship study indicated that any structural modifications of auriculatone would reduce the activity. Computer-aided molecular docking showed that, CYP450 might be the target of auriculatone. The hepatoprotective effect of auriculatone might be elicited through suppression of the CYP450 activity, which further reduces the generation of toxic metabolite NAPQI of APAP. Conclusion: Auriculatone is a promising hepatoprotective agent worthy of further research and development. Its hepatoprotective effect may involve the metabolic suppression of CYP450 to reduce the toxic metabolite of APAP.