A pilot study of the effects of d-alpha-tocopherol on hepatic stellate cell activation in chronic hepatitis C.
OBJECTIVE
Oxidative stress mediates activation and stimulates collagen production of cultured hepatic stellate (Ito) cells. The aim of this study was to assess whether oxidative stress contributes to hepatic fibrogenesis in chronic hepatitis C.


METHODS
In liver biopsy specimens of patients with chronic hepatitis C, the following fibrogenesis cascade was analyzed: (1) oxidative stress, determined by the presence of malondialdehyde protein adducts; (2) activation of stellate cells as indicated by their expression of alpha-smooth muscle actin; (3) stimulation of c-myb expression in stellate cells, a critical step in the activation of these cells; and (4) induction of collagen gene expression as detected by in situ hybridization.


RESULTS
Treatment with d-alpha-tocopherol (1200 IU/day for 8 weeks) in 6 of these patients, who were refractory to interferon therapy, prevented the fibrogenesis cascade observed before antioxidant treatment. In addition, d-alpha-tocopherol treatment significantly decreased the carbonyl modifications of plasma proteins, a sensitive index of oxidative stress. However, 8 weeks of d-alpha-tocopherol treatment did not significantly affect serum alanine aminotransferase levels, hepatitis C virus titers, or histological degree of hepatocellular inflammation or fibrosis.


CONCLUSIONS
These data suggest that enhanced oxidative stress initiates a fibrogenesis cascade in the liver of patients with chronic hepatitis C.
Houglum
K
K
Department of Medicine, Veterans Affairs Medical Center, San Diego, California, USA.
Venkataramani
A
A
Lyche
K
K
Chojkier
M
M
D000199:Actins / Q000096:biosynthesis; D001706:Biopsy; D003094:Collagen / Q000096:biosynthesis; D005260:Female; D006526:Hepatitis C / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D017403:In Situ Hybridization; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D008875:Middle Aged; D018384:Oxidative Stress; D010865:Pilot Projects; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D020598:Proto-Oncogene Proteins c-myb; D011519:Proto-Oncogenes; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D015534:Trans-Activators / Q000096:biosynthesis; D014158:Transcription, Genetic; D014810:Vitamin E / Q000627:therapeutic use*
D000199:Actins; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D012333:RNA, Messenger; D015534:Trans-Activators; D014810:Vitamin E; D008315:Malondialdehyde; D003094:Collagen