Discovery and structure-activity relationship of auriculatone: A potent hepatoprotective agent against acetaminophen-induced liver injury

Acetaminophen (APAP, paracetamol) overdose has been the most frequent cause of drug-induced liver failure. APAP-induced liver toxicity can be fatal in many cases even with treatment of the clinically used N-acetylcysteine (NAC), and the need for novel therapeutic agents is apparent. Through evaluating the hepatoprotective effects of the co-occurring substances present in oleanolic acid tablets which have been used in China for decades as an adjuvant therapy for acute and chronic hepatitis, auriculatone was found to protect HL-7702 cells from APAP-induced liver injury comparable to NAC at the concentration of 10 mu M. Structure activity relationship on auriculatone and its analogs showed that absence of the C17 carboxyl group of auriculatone was essential to achieve good hepatoprotective activity, and that the C3-OH, C16 carbonyl and C12-C13 olefinic group were critical for retaining the exceptional activity of auriculatone. Any modifications in the current investigation were all detrimental to the hepatoprotective activity. Docking and drug-metabolizing activity studies demonstrated that CYP3A4 was likely the main target of auriculatone, and that auriculatone elicited the hepatoprotective effect possibly through inhibiting CYP3A4's metabolism of APAP to the toxic metabolite NAPQI. The work may pave the way for the use of auriculatone in the treatment of APAP-induced liver injury. (C) 2017 Elsevier Ltd. All rights reserved.