Glycine N-methyltransferase affects the metabolism of aflatoxin B{sub 1} and blocks its carcinogenic effect
- Division of Molecular Medicine, Institute of Public Health, School of Medicine, National Yang-Ming University, Taipei, Taiwan (China)
- AIDS Prevention and Research Center, National Yang-Ming University, Taipei, Taiwan (China)
- National Research Institute of Chinese Medicine, Taipei, Taiwan (China)
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan (China)
- Faculty of Life Sciences and Institute of Genome, National Yang-Ming University, Taipei, Taiwan (China)
- Biomolecular Structure Section, Macromolecular Crystallography Laboratory, National Cancer Institute-Frederick, Frederick, Maryland 21701 (United States)
- Department of Public Health, Chang-Gung University, Tao-Yuan, Taiwan (China)
Previously, we reported that glycine N-methyltransferase (GNMT) knockout mice develop chronic hepatitis and hepatocellular carcinoma (HCC) spontaneously. For this study we used a phosphoenolpyruvate carboxykinase promoter to establish a GNMT transgenic (TG) mouse model. Animals were intraperitoneally inoculated with aflatoxin B{sub 1} (AFB{sub 1}) and monitored for 11 months, during which neither male nor female GNMT-TG mice developed HCC. In contrast, 4 of 6 (67%) male wild-type mice developed HCC. Immunofluorescent antibody test showed that GNMT was translocated into nuclei after AFB{sub 1} treatment. Competitive enzyme immunoassays indicated that after AFB{sub 1} treatment, the AFB{sub 1}-DNA adducts formed in stable clones expressing GNMT reduced 51.4% compared to the vector control clones. Experiments using recombinant adenoviruses carrying GNMT cDNA (Ad-GNMT) further demonstrated that the GNMT-related inhibition of AFB{sub 1}-DNA adducts formation is dose-dependent. HPLC analysis of the metabolites of AFB{sub 1} in the cultural supernatants of cells exposed to AFB{sub 1} showed that the AFM{sub 1} level in the GNMT group was significantly higher than the control group, indicating the presence of GNMT can enhance the detoxification pathway of AFB{sub 1}. Cytotoxicity assay showed that the GNMT group had higher survival rate than the control group after they were treated with AFB{sub 1}. Automated docking experiments showed that AFB{sub 1} binds to the S-adenosylmethionine binding domain of GNMT. Affinity sensor assay demonstrated that the dissociation constant for GNMT-AFB{sub 1} interaction is 44.9 {mu}M. Therefore, GNMT is a tumor suppressor for HCC and it exerts protective effects in hepatocytes via direct interaction with AFB{sub 1}, resulting in reduced AFB{sub 1}-DNA adducts formation and cell death.
- OSTI ID:
- 21182756
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 235, Issue 3; Other Information: DOI: 10.1016/j.taap.2008.12.013; PII: S0041-008X(08)00524-3; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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