Dimethyl ester of bilirubin exhibits anti-inflammatory activity through inhibition of secretory phospholipase A2, lipoxygenase and cyclooxygenase

Joshi, Vikram and Umashankara, M. and Ramakrishnan, Chandrasekaran and Nanjaraj Urs, A. N. and Suvilesh, Kanve Nagaraj and Velmurugan, Devadasan and Rangappa, K. S. and Vishwanath, B. S. (2016) Dimethyl ester of bilirubin exhibits anti-inflammatory activity through inhibition of secretory phospholipase A2, lipoxygenase and cyclooxygenase. Archives of Biochemistry and Biophysics, 598. 28 - 39.

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Official URL: https://doi.org/10.1016/j.abb.2016.04.003

Abstract

Overproduction of arachidonic acid (AA) mediated by secretory phospholipase A2 group IIA (sPLA2IIA) 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 sPLA2IIA, 5-LOX and COX-1/2 activities is critical in regulating inflammation. We have previously reported unconjugated bilirubin (UCB), an endogenous antioxidant, as sPLA2IIA inhibitor. However, lipophilic UCB gets conjugated in liver with glucuronic acid into hydrophilic conjugated bilirubin (CB). Since hydrophobicity is pre-requisite for sPLA2IIA inhibition, conjugation reduces the efficacy of UCB. In this regard, UCB was chemically modified and derivatives were evaluated for sPLA2IIA, 5-LOX and COX-1/2 inhibition. Among the derivatives, BD1 (dimethyl ester of bilirubin) exhibited ∼ 3 fold greater inhibitory potency towards sPLA2IIA 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 BD1 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.

Item Type: Article
Uncontrolled Keywords: Anti-inflammation, Arachidonic acid, Bilirubin dimethyl ester, Phospholipase A, Unconjugated bilirubin
Subjects: C Chemical Science > Biochemistry
C Chemical Science > Chemistry
Divisions: Department of > Biochemistry
Department of > Chemistry
Depositing User: manjula User
Date Deposited: 21 Jun 2019 07:54
Last Modified: 21 Jun 2019 07:54
URI: http://eprints.uni-mysore.ac.in/id/eprint/3593

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