title: Dimethyl ester of bilirubin exhibits anti-inflammatory activity through inhibition of secretory phospholipase A2, lipoxygenase and cyclooxygenase.
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.
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysuru, Karnataka, India.
authors.forename: Vikram
authors.initials: V
authors.lastname: Joshi
authors.affiliation: Department of Chemistry, Karnataka State Open University, Mukthagangotri, Mysuru, Karnataka, India.
authors.forename: M
authors.initials: M
authors.lastname: Umashankara
authors.affiliation: Centre of Advanced Study in Crystallography and Biophysics, University of Madras, Guindy Campus, Chennai, Tamil Nadu, India.
authors.forename: Chandrasekaran
authors.initials: C
authors.lastname: Ramakrishnan
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysuru, Karnataka, India.
authors.forename: Ankanahalli N
authors.initials: AN
authors.lastname: Nanjaraj Urs
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysuru, Karnataka, India.
authors.forename: Kanve Nagaraj
authors.initials: KN
authors.lastname: Suvilesh
authors.affiliation: Centre of Advanced Study in Crystallography and Biophysics, University of Madras, Guindy Campus, Chennai, Tamil Nadu, India; Bioinformatics Infrastructure Facility, University of Madras, Guindy Campus, Chennai, Tamil Nadu, India.
authors.forename: Devadasan
authors.initials: D
authors.lastname: Velmurugan
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysuru, Karnataka, India.
authors.forename: Kanchugarakoppal S
authors.initials: KS
authors.lastname: Rangappa
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysuru, Karnataka, India. Electronic address: vishmy@yahoo.co.uk.
authors.forename: Bannikuppe Sannanaik
authors.initials: BS
authors.lastname: Vishwanath
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D001663:Bilirubin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D001792:Blood Platelets / Q000201:enzymology; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D054497:Phospholipases A2, Secretory / Q000037:antagonists & inhibitors / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D052246:Cyclooxygenase 2 Inhibitors; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; C032217:bilirubin dimethyl ester; D001094:Arachidonate 5-Lipoxygenase; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; C496512:Ptgs1 protein, mouse; D054497:Phospholipases A2, Secretory; D001663:Bilirubin
keywords: Anti-inflammation; Arachidonic acid; Bilirubin dimethyl ester; Phospholipase A(2); Unconjugated bilirubin