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Cytochromes P-450 in human hepatocyte plasma membrane: recognition by several autoantibodies
J Loeper1, V Descatoire, M Maurice
1Institut National de la Santé et de la Recherche Médicale: Unit 24, Clichy, France.
Background:
Anti-cytochrome P-450 autoantibodies are present in several forms of autoimmune hepatitis. The possibility that cytochromes P-450 are present in the plasma membrane of human hepatocytes was examined.
Methods:
(1) Plasma membranes with microsomal contamination < 1%, as judged from the activities of glucose-6-phosphatase and NADH-cytochrome c reductase, were prepared. (2) After exposure of uncut, fixed hepatocytes to antibodies, immunofluorescence and immunoperoxidase studies were performed.
Results:
(1) The specific content of cytochrome P-450 in plasma membrane was 9% of that in microsomes. Plasma membranes showed NADPH-cytochrome c reductase and mono-oxygenase activities; immunoblots showed the presence of cytochromes P-450 1A2, 2C, 2D6, 2E1, and 3A4; cytochromes P-450 1A2, 2D6, and 2C were also recognized by anti-liver microsome and anti-liver/kidney microsome type 1 and type 2 autoantibodies, respectively. (2) Immunofluorescence and immunoperoxidase labeling of the plasma membrane was observed with the three auto-antibodies and with anti-cytochrome P-450 1A2, 2C, 2E1, or 3A4.
Conclusions:
It is concluded that cytochromes P-450 are present and functional in the plasma membrane of human hepatocytes and that anti-cytochrome P-450 autoantibodies recognize epitopes expressed on the outer surface.
Insights
This study found that cytochrome P-450 enzymes are present and active in human hepatocyte plasma membranes. Autoantibodies associated with autoimmune hepatitis recognize these membrane-bound cytochromes P-450.
Area of Science:
- Hepatology
- Immunology
- Biochemistry
Background:
- Autoimmune hepatitis is associated with anti-cytochrome P-450 autoantibodies.
- The cellular localization of cytochrome P-450 enzymes in human hepatocytes was investigated.
Purpose of the Study:
- To determine if cytochromes P-450 are present in the plasma membrane of human hepatocytes.
- To investigate the recognition of these membrane-bound cytochromes by autoantibodies.
Main Methods:
- Isolation of highly pure plasma membranes from human hepatocytes.
- Immunofluorescence and immunoperoxidase labeling of fixed hepatocytes and isolated plasma membranes using specific autoantibodies and anti-cytochrome P-450 antibodies.
Main Results:
- Cytochromes P-450 were detected in the plasma membrane, exhibiting enzymatic activity.
- Specific cytochrome P-450 isoforms (1A2, 2C, 2D6, 2E1, 3A4) were identified.
- Autoantibodies recognized cytochrome P-450 epitopes on the hepatocyte plasma membrane.
Conclusions:
- Cytochromes P-450 are functional components of the human hepatocyte plasma membrane.
- Anti-cytochrome P-450 autoantibodies target epitopes on the external surface of hepatocytes.
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