Evidence for induced microsomal bilirubin degradation by cytochrome P450 2A5

Abu-Bakar, A’edah, Moore, Michael R. and Lang, Matti A. (2005) Evidence for induced microsomal bilirubin degradation by cytochrome P450 2A5. Biochemical Pharmacology, 70 10: 1527-1535. doi:10.1016/j.bcp.2005.08.009


Author Abu-Bakar, A’edah
Moore, Michael R.
Lang, Matti A.
Title Evidence for induced microsomal bilirubin degradation by cytochrome P450 2A5
Journal name Biochemical Pharmacology   Check publisher's open access policy
ISSN 0006-2952
1873-2968
Publication date 2005-11-15
Sub-type Article (original research)
DOI 10.1016/j.bcp.2005.08.009
Volume 70
Issue 10
Start page 1527
End page 1535
Total pages 9
Place of publication New York, USA
Publisher Elsevier
Collection year 2005
Language eng
Subject 11 Medical and Health Sciences
Abstract Oxidative metabolism of bilirubin (BR) - a breakdown product of haem with cytoprotective and toxic properties - is an important route of detoxification in addition to glucuronidation. The major enzyme(s) involved in this oxidative degradation are not known. In this paper, we present evidence for a major role of the hepatic cytochrome P450 2A5 (Cyp2a5) in BR degradation during cadmium intoxication, where the BR levels are elevated following induction of haem oxygenase-1 (HO-1). Treatment of DBA/2J mice with CdCl2 induced both the Cyp2a5 and HO-1, and increased the microsomal BR degradation activity. By contrast, the total cytochrome P450 (CYP) content and the expression of Cyp1a2 were down-regulated by the treatment. The induction of the HO-1 and Cyp2a5 was substantial at the mRNA, protein and enzyme activity levels. In each case, the up-regulation of HO-1 preceded that of Cyp2a5 with a 5-10 h interval. BR totally inhibited the microsomal Cyp2a5-dependent coumarin hydroxylase activity, with an IC50 approximately equal to the substrate concentration. The 7-methoxyresorufin 7-O-demethylase (MROD) activity, catalyzed mainly by the Cyp1a2, was inhibited up to 36% by BR. The microsomal BR degradation was inhibited by coumarin and a monoclonal antibody against the Cyp2a5 by about 90%. Furthermore, 7-methoxyresorufin, a substrate for the Cyp1a2, inhibited BR degradation activity by approximately 20%. In sum, the results strongly suggest a major role for Cyp2a5 in the oxidative degradation of BR. Secondly, the coordinated up-regulation of the HO-1 and Cyp2a5 during Cd-mediated injury implicates a network of enzyme systems in the maintenance of balancing BR production and elimination.
Keyword Pharmacology & Pharmacy
Cadmium
Cytochrome P450 2a5
Alternative Pathway Of Bilirubin Degradation
Haem Oxygenase 1
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
National Research Centre for Environmental Toxicology Publications
 
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Created: Wed, 15 Aug 2007, 06:57:38 EST