Mitochondrial targeting of bilirubin regulatory enzymes: an adaptive response to oxidative stress

Muhsain, Siti Nur Fadzilah, Lang, Matti A. and Abu-Bakar, A'edah (2015) Mitochondrial targeting of bilirubin regulatory enzymes: an adaptive response to oxidative stress. Toxicology and Applied Pharmacology, 282 1: 77-89. doi:10.1016/j.taap.2014.11.010

Author Muhsain, Siti Nur Fadzilah
Lang, Matti A.
Abu-Bakar, A'edah
Title Mitochondrial targeting of bilirubin regulatory enzymes: an adaptive response to oxidative stress
Journal name Toxicology and Applied Pharmacology   Check publisher's open access policy
ISSN 1096-0333
Publication date 2015-01-01
Year available 2014
Sub-type Article (original research)
DOI 10.1016/j.taap.2014.11.010
Open Access Status
Volume 282
Issue 1
Start page 77
End page 89
Total pages 13
Place of publication Maryland Heights, MO United States
Publisher Academic Press
Collection year 2015
Language eng
Abstract The intracellular level of bilirubin (BR), an endogenous antioxidant that is cytotoxic at high concentrations, is tightly controlled within the optimal therapeutic range. We have recently described a concerted intracellular BR regulation by two microsomal enzymes: heme oxygenase 1 (HMOX1), essential for BR production and cytochrome P450 2A5 (CYP2A5), a BR oxidase. Herein, we describe targeting of these enzymes to hepatic mitochondria during oxidative stress. The kinetics of microsomal and mitochondrial BR oxidation were compared. Treatment of DBA/2J mice with 200 mg pyrazole/kg/day for 3 days increased hepatic intracellular protein carbonyl content and induced nucleo-translocation of Nrf2. HMOX1 and CYP2A5 proteins and activities were elevated in microsomes and mitoplasts but not the UGT1A1, a catalyst of BR glucuronidation. A CYP2A5 antibody inhibited 75% of microsomal BR oxidation. The inhibition was absent in control mitoplasts but elevated to 50% after treatment. An adrenodoxin reductase antibody did not inhibit microsomal BR oxidation but inhibited 50% of mitochondrial BR oxidation. Ascorbic acid inhibited 5% and 22% of the reaction in control and treated microsomes, respectively. In control mitoplasts the inhibition was 100%, which was reduced to 50% after treatment. Bilirubin affinity to mitochondrial and microsomal CYP2A5 enzyme is equally high. Lastly, the treatment neither released cytochrome c into cytoplasm nor dissipated membrane potential, indicating the absence of mitochondrial membrane damage. Collectively, the observations suggest that BR regulatory enzymes are recruited to mitochondria during oxidative stress and BR oxidation by mitochondrial CYP2A5 is supported by mitochondrial mono-oxygenase system. The induced recruitment potentially confers membrane protection.
Keyword Mitochondria
Oxidative stress
Endoplasmic reticulum
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online ahead of print 3 Nov 2014

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
National Research Centre for Environmental Toxicology Publications
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Citation counts: TR Web of Science Citation Count  Cited 4 times in Thomson Reuters Web of Science Article | Citations
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