28 March 2016 : Animal Research
The Cooperative Effect of Local Angiotensin-II in Liver with Adriamycin Hepatotoxicity on MitochondriaEylem TaskinABCDEFG, Celal GuvenDEF, Leyla SahinDEF, Nurcan DursunABCDEFG
Med Sci Monit 2016; 22:1013-1021
BACKGROUND: Adriamycin (ADR) is a drug used clinically for anticancer treatment; however, it causes adverse effects in the liver. The mechanism by which these adverse effects occur remains unclear, impeding efforts to enhance the therapeutic effects of ADR. Its hepatotoxicity might be related to increasing reactive oxygen species (ROS) and mitochondrial dysfunction. The interaction between ADR and the local renin-angiotensin system (RAS) in the liver is unclear. ADR might activate the RAS. Angiotensin-II (Ang-II) leads to ROS production and mitochondrial dysfunction. In the present study we investigated whether ADR’s hepatotoxicity interacts with local RAS in causing oxidative stress resulting from mitochondrial dysfunction in the rat liver.
MATERIAL AND METHODS: Rats were divided into 5 groups: control, ADR, co-treated ADR with captopril, co-treated ADR with Aliskiren, and co-treated ADR with both captopril and Aliskiren. Mitochondria and cytosol were separated from the liver, then biochemical measurements were made from them. Mitochondrial membrane potential (MMP) and ATP levels were evaluated.
RESULTS: ADR remarkably decreased MMP and ATP in liver mitochondria (p<0.05). Co-administration with ADR and Aliskiren and captopril improved the dissipation of MMP (p<0.05). The decreased ATP level was restored by treatment with inhibitors of ACE and renin.
CONCLUSIONS: Angiotensin-II may contribute to hepatotoxicity of in the ADR via mitochondrial oxidative production, resulting in the attenuation of MMP and ATP production.
Keywords: Angiotensin II - pharmacology, Adenosine Triphosphate - metabolism, Cytosol - metabolism, Doxorubicin - adverse effects, Liver - pathology, Membrane Potential, Mitochondrial - drug effects, Mitochondria, Liver - metabolism, Oxidative Stress - drug effects
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