| First Author | Abu-Bakar A | Year | 2005 |
| Journal | Biochem Pharmacol | Volume | 70 |
| Issue | 10 | Pages | 1527-35 |
| PubMed ID | 16183037 | Mgi Jnum | J:102659 |
| Mgi Id | MGI:3607883 | Doi | 10.1016/j.bcp.2005.08.009 |
| Citation | Abu-Bakar A, et al. (2005) Evidence for induced microsomal bilirubin degradation by cytochrome P450 2A5. Biochem Pharmacol 70(10):1527-35 |
| abstractText | 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 CdCl(2) 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 5-10h interval. BR totally inhibited the microsomal Cyp2a5-dependent coumarin hydroxylase activity, with an IC(50) 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. |
