The mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients.
BACKGROUND
Increased oxidative stress and subsequent mitochondrial damage are important pathways for liver damage in chronic hepatitis C virus (HCV) infection; consequently, therapies that decrease mitochondrial oxidative damage may improve outcome. The mitochondria-targeted anti-oxidant mitoquinone combines a potent anti-oxidant with a lipophilic cation that causes it to accumulate several-hundred fold within mitochondria in vivo.


OBJECTIVE
In this phase II study, we investigated the effect of oral mitoquinone on serum aminotransferases and HCV RNA levels in HCV-infected patients.


METHODS
Thirty HCV patients who were either non-responders or unsuitable candidates for standard-of-care (pegylated interferon plus ribavirin) were randomized to receive mitoquinone (40 or 80 mg) or placebo once daily for 28 days, and serum aminotransferases and HCV RNA levels were measured.


RESULTS
Both treatment groups showed significant decreases in absolute and percentage changes in serum alanine transaminase (ALT) from baseline to treatment day 28 (P<0.05). There was also a significant difference between incremental area under the curve for ALT between baseline and day 28 for the 40 mg treatment group against placebo (P<0.05). The differences in plasma ALT activity from baseline to day 28 in both mitoquinone groups compared with placebo did not reach significance (P>0.05). There was no change in HCV load on mitoquinone treatment.


CONCLUSIONS
Administration of the mitochondria-targeted anti-oxidant mitoquinone significantly decreased plasma ALT and aspartate aminotransferase in patients with chronic HCV infection, and this suggests that mitoquinone may decrease necroinflammation in the liver in these patients. As mitochondrial oxidative damage contributes to many other chronic liver diseases, such as steatohepatitis, further studies using mitochondria-targeted anti-oxidants in HCV and other liver diseases are warranted.
Gane
Edward J
EJ
Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand. EdGane@adhb.govt.nz
Weilert
Frank
F
Orr
David W
DW
Keogh
Geraldine F
GF
Gibson
Michael
M
Lockhart
Michelle M
MM
Frampton
Christopher M
CM
Taylor
Kenneth M
KM
Smith
Robin A J
RA
Murphy
Michael P
MP
D000284:Administration, Oral; D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000975:Antioxidants / Q000008:administration & dosage / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007372:Interferons / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D012254:Ribavirin / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome; D014451:Ubiquinone / Q000008:administration & dosage / Q000627:therapeutic use* / Q000031:analogs & derivatives; D019562:Viral Load
D000975:Antioxidants; D000998:Antiviral Agents; D015415:Biomarkers; D009943:Organophosphorus Compounds; D012367:RNA, Viral; D014451:Ubiquinone; C429014:mitoquinone; D012254:Ribavirin; D007372:Interferons; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase