Inducible bilirubin oxidase: A novel function for the mouse cytochrome P450 2A5

Abu-Bakar, A'edah, Arthur, Dionne Maioha, Aganovic, Simona, Ng, Jack C. and Lang, Matti A. (2011) Inducible bilirubin oxidase: A novel function for the mouse cytochrome P450 2A5. Toxicology and Applied Pharmacology, 257 1: 14-22. doi:10.1016/j.taap.2011.08.011

Author Abu-Bakar, A'edah
Arthur, Dionne Maioha
Aganovic, Simona
Ng, Jack C.
Lang, Matti A.
Title Inducible bilirubin oxidase: A novel function for the mouse cytochrome P450 2A5
Journal name Toxicology and Applied Pharmacology   Check publisher's open access policy
ISSN 0041-008X
Publication date 2011-11-15
Sub-type Article (original research)
DOI 10.1016/j.taap.2011.08.011
Volume 257
Issue 1
Start page 14
End page 22
Total pages 9
Place of publication Maryland Heights, MO, United States
Publisher Academic Press
Collection year 2012
Language eng
Formatted abstract
We have previously shown that bilirubin (BR), a breakdown product of haem, is a strong inhibitor and a high affinity substrate of the mouse cytochrome P450 2A5 (CYP2A5). The antioxidant BR, which is cytotoxic at high concentrations, is potentially useful in cellular protection against oxygen radicals if its intracellular levels can be strictly controlled. The mechanisms that regulate cellular BR levels are still obscure. In this paper we provide preliminary evidence for a novel function of CYP2A5 as hepatic “BR oxidase”. A high-performance liquid chromatography/electrospray ionisation mass spectrometry screening showed that recombinant yeast microsomes expressing the CYP2A5 oxidise BR to biliverdin, as the main metabolite, and to three other smaller products with m/z values of 301, 315 and 333. The metabolic profile is significantly different from that of chemical oxidation of BR. In chemical oxidation the smaller products were the main metabolites. This suggests that the enzymatic reaction is selective, towards biliverdin production. Bilirubin treatment of primary hepatocytes increased the CYP2A5 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 CYP2A5 compared to cells treated only with CHX. Collectively, the observations suggest that the CYP2A5 is potentially an inducible “BR oxidase” where BR may accelerate its own metabolism through stabilization of the CYP2A5 protein. It is possible that this metabolic pathway is potentially part of the machinery controlling intracellular BR levels in transient oxidative stress situations, in which high amounts of BR are produced.
Keyword Cytochrome P450
Bilirubin oxidation
Oxidative stress
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
National Research Centre for Environmental Toxicology Publications
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