L-carnitine inhibits hepatocarcinogenesis via protection of mitochondria.
Hepatocellular carcinoma is usually preceded by chronic inflammation. However, the molecular mechanism in hepatocarcinogenesis is not well known. Recently, we reported that mitochondrial dysfunction plays an important role in hepatocarcinogenesis via the production of free radicals. Furthermore, we proved that L-carnitine effectively protects mitochondrial function in vivo. Therefore, we investigated whether long-term administration of L-carnitine could prevent hepatitis and subsequent hepatocellular carcinoma in Long-Evans Cinnamon rats that are often analyzed as a model of hepatocarcinogenesis. The results indicated that oxidative stress elicited from abnormally accumulated copper increased the amount of free fatty acids, thereby inducing mitochondrial dysfunction, resulting in cell death and enhanced secondary generation of reactive oxygen species, which were significantly inhibited by carnitine treatment. Finally, the occurrence of placental glutathione S-transferase-positive foci as a marker for preneoplastic lesions and hepatocarcinogenesis were significantly inhibited by L-carnitine. These facts suggest that mitochondrial injury plays an essential role in the development of hepatocarcinogenesis and that the clinical use of carnitine has excellent therapeutic potential in individuals with chronic hepatitis.
Chang
Baojun
B
Department of Biochemistry and Molecular Pathology, Osaka City University Medical School, Osaka, Japan.
Nishikawa
Manabu
M
Nishiguchi
Shuhei
S
Inoue
Masayasu
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000517:prevention & control*; D002331:Carnitine / Q000627:therapeutic use*; D003300:Copper / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006505:Hepatitis / Q000517:prevention & control; D008113:Liver Neoplasms / Q000517:prevention & control*; D008297:Male; D008928:Mitochondria / Q000187:drug effects*; D018384:Oxidative Stress; D010920:Placenta / Q000201:enzymology; D051381:Rats; D020332:Rats, Inbred LEC; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism
D005230:Fatty Acids, Nonesterified; D017382:Reactive Oxygen Species; D003300:Copper; D005982:Glutathione Transferase; D002331:Carnitine