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Metabolism of bilirubin by human cytochrome P450 2A6
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
Vise andre og tillknytning
2012 (engelsk)Inngår i: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 261, nr 1, s. 50-58Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The mouse cytochrome P450 (CYP) 2A5 has recently been shown to function as hepatic "Bilirubin Oxidase" (Abu-Bakar, A., et al., 2011. Toxicol. Appl. Pharmacol. 257, 14-22). To date, no information is available on human CYP isoforms involvement in bilirubin metabolism. In this paper we provide novel evidence for human CYP2A6 metabolising the tetrapyrrole bilirubin. Incubation of bilirubin with recombinant yeast microsomes expressing the CYP2A6 showed that bilirubin inhibited CYP2A6-dependent coumarin 7-hydroxylase activity to almost 100% with an estimated K-i of 2.231 mu M. Metabolite screening by a high-performance liquid chromatography/electrospray ionisation mass spectrometry indicated that CYP2A6 oxidised bilirubin to biliverdin and to three other smaller products with m/z values of 301,315 and 333. Molecular docking analyses indicated that bilirubin and its positively charged intermediate interacted with key amino acid residues at the enzyme's active site. They were stabilised at the site in a conformation favouring biliverdin formation. By contrast, the end product, biliverdin was less fitting to the active site with the critical central methylene bridge distanced from the CYP2A6 haem iron facilitating its release. Furthermore, bilirubin treatment of HepG2 cells increased the CYP2A6 protein and activity levels with no effect on the corresponding mRNA. Co-treatment with cycloheximide (CHX), a protein synthesis inhibitor, resulted in increased half-life of the CYP2A6 compared to cells treated only with CHX. Collectively, the observations indicate that the CYP2A6 may function as human "Bilirubin Oxidase" where bilirubin is potentially a substrate and a regulator of the enzyme.

sted, utgiver, år, opplag, sider
2012. Vol. 261, nr 1, s. 50-58
Emneord [en]
CYP2A6, Bilirubin oxidation, HPLC/ESI-MS, Bilirubin oxidase, Molecular docking, Oxidative stress
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-253291DOI: 10.1016/j.taap.2012.03.010ISI: 000304494600006PubMedID: 22465937OAI: oai:DiVA.org:uu-253291DiVA, id: diva2:813993
Tilgjengelig fra: 2015-05-25 Laget: 2015-05-25 Sist oppdatert: 2018-01-11bibliografisk kontrollert

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