Interaction of bile pigments and 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) with CYP2A6 and CYP2A13 / Nurnadia Majid

Bilirubin and biliverdin are bile pigments produced from the breakdown of senescent red blood cells. Other than mainly known to aid in the digestion of fats, the free radical scavenging property and the inverse relationship between serum bilirubin levels and cancer risk has been widely reported. The 4-(methylnitrosamino)-1-(3-pyridyl)-1butanone (NNK) is a procarcinogen found in tobacco smoke. Metabolism of NNK mediated by CYP2A6 and CYP2A13 resulted in formation of free radical with DNA damaging property. Inhibitor of NNK metabolism has been of interest to decrease the production of free radicals that contribute to the development of tobacco products induced lung cancer. The interactions of bile pigments with CYP2A6 and CYP2A13 enzymes still largely unknown. Fundamental knowledge on the interaction of bile pigments and NNK with CYP2A6 and CYP2A13 enzymes, is important as part of understanding the protective role of bile pigments in human during NNK-induced carcinogenesis. Therefore, in this study, the interaction of bile pigments with the active site and other possible binding sites in the enzyme structures of CYP2A6 and CYP2A13 was explored. The inhibitory effect of bilirubin and NNK on the coumarin 7hydroxylation mediated by CYP2A6 was also investigated. Molecular docking using AutoDock (ADV) software was performed to computationally dock the bile pigments to the active sites of CYP2A6 and CYP2A13 enzymes. Next, the interactions between the top docked poses of ligands produced by ADV was visualized by PyMOL and PoseView software. Based on the binding energy, NNK exhibited lower binding energy to active sites of CYP2A6 compared to bile pigments, but bile pigments exhibited lower binding energy to CYP2A13 active sites than NNK. Nevertheless, the ligands were found interacted with key amino acid residues at the active sites of CYP2A6 and CYP2A13 crystal structures. DoGSiteScorer was used to predict allosteric sites of both enzymes.