Dimethyl ester of bilirubin exhibits anti-inflammatory activity through inhibition of secretory phospholipase A(2), lipoxygenase and cyclooxygenase

作者：Joshi Vikram; Umashankara M; Ramakrishnan Chandrasekaran; Urs Ankanahalli N Nanjaraj; Suvilesh Kanve Nagaraj; Velmurugan Devadasan; Rangappa Kanchugarakoppal S; Vishwanath Bannikuppe Sannanaik

来源：Archives of Biochemistry and Biophysics, 2016, 598: 28-39.

DOI：10.1016/j.abb.2016.04.003

• Anti-inflammation
• Arachidonic acid
• Bilirubin dimethyl ester
• Phospholipase A(2)
• Unconjugated bilirubin

Overproduction of arachidonic acid (AA) mediated by secretory phospholipase A(2) group IIA (sPLA(2)IIA) is a hallmark of many inflammatory disorders. AA is subsequently converted into pro-inflammatory eicosanoids through 5-lipoxygenase (5-LOX) and cyclooxygenase-1/2 (COX-1/2) activities. Hence, inhibition of sPLA(2)IIA, 5-LOX and COX-1/2 activities is critical in regulating inflammation. We have previously reported unconjugated bilirubin (UCB), an endogenous antioxidant, as sPLA(2)IIA inhibitor. However, lipophilic UCB gets conjugated in liver with glucuronic acid into hydrophilic conjugated bilirubin (CB). Since hydrophobicity is pre-requisite for sPLA(2)IIA inhibition, conjugation reduces the efficacy of UCB. In this regard, UCB was chemically modified and derivatives were evaluated for sPLA(2)IIA, 5-LOX and COX-1/2 inhibition. Among the derivatives, BD1 (dimethyl ester of bilirubin) exhibited 3 fold greater inhibitory potency towards sPLA(2)IIA compared to UCB. Both UCB and BD1 inhibited human 5-LOX and COX-2 activities; however only BD1 inhibited AA induced platelet aggregation. Molecular docking studies demonstrated BDI as better inhibitor of aforesaid enzymes than UCB and other endogenous antioxidants. These data suggest that BD1 exhibits strong anti-inflammatory activity through inhibition of AA cascade enzymes which is of great therapeutic importance.

• 出版日期2016-5-15