TY - JOUR
T1 - The multi-functional roles of GNMT in toxicology and cancer
AU - Yen, Chia Hung
AU - Lin, Yu Ting
AU - Chen, Heng Li
AU - Chen, Shih Yin
AU - Chen, Yi Ming Arthur
N1 - Funding Information:
This work was supported in part by grants from the National Science Council of the Republic of China (National Research Program for Biopharmaceuticals [NRPB] , grant NSC100-2325-B-010-008 ).
PY - 2013/1/1
Y1 - 2013/1/1
N2 - Although glycine N-methyltransferase (GNMT) has been discovered for five decades, its function was not elucidated until recently. In this review, we discuss the multiple roles of GNMT in toxicology and cancer. Besides catalyzing the production of methylglycine (sarcosine) in one carbon metabolism pathway, GNMT was found to be able to bind a number of polycyclic aromatic hydrocarbons and inhibit DNA adducts formation. Moreover, GNMT exerts protective effects against the cytotoxicity and carcinogenicity of benzo(a)pyrene and aflatoxin B1 in vitro and in vivo. Occupational study showed that workers who had genotypes with higher GNMT promoter activity may have lower content of oxidative damaged DNA products in their urine. In terms of cancer, recent studies using GNMT knockout mouse models demonstrated that GNMT deficiency has high penetrance in inducing the development of steatohepatitis and hepatocellular carcinoma. In terms of the mechanism, besides dysregulation of epigenetic modification, insights have been provided by recent identification of two novel proteins interacting with GNMT-DEPTOR and NPC2. These studies suggest that GNMT not only is involved in mTOR signaling pathway, but also plays an important role in the intracellular trafficking of cholesterol. The implication of these findings to the preventive medicine and translational research will be discussed.
AB - Although glycine N-methyltransferase (GNMT) has been discovered for five decades, its function was not elucidated until recently. In this review, we discuss the multiple roles of GNMT in toxicology and cancer. Besides catalyzing the production of methylglycine (sarcosine) in one carbon metabolism pathway, GNMT was found to be able to bind a number of polycyclic aromatic hydrocarbons and inhibit DNA adducts formation. Moreover, GNMT exerts protective effects against the cytotoxicity and carcinogenicity of benzo(a)pyrene and aflatoxin B1 in vitro and in vivo. Occupational study showed that workers who had genotypes with higher GNMT promoter activity may have lower content of oxidative damaged DNA products in their urine. In terms of cancer, recent studies using GNMT knockout mouse models demonstrated that GNMT deficiency has high penetrance in inducing the development of steatohepatitis and hepatocellular carcinoma. In terms of the mechanism, besides dysregulation of epigenetic modification, insights have been provided by recent identification of two novel proteins interacting with GNMT-DEPTOR and NPC2. These studies suggest that GNMT not only is involved in mTOR signaling pathway, but also plays an important role in the intracellular trafficking of cholesterol. The implication of these findings to the preventive medicine and translational research will be discussed.
KW - Detoxification
KW - Functional diversity
KW - Glycine N-methyltransferase
KW - Hepatocellular carcinoma
KW - Polycyclic aromatic hydrocarbon
KW - Signal transduction
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U2 - 10.1016/j.taap.2012.11.003
DO - 10.1016/j.taap.2012.11.003
M3 - Review article
C2 - 23147572
AN - SCOPUS:84870223616
SN - 0041-008X
VL - 266
SP - 67
EP - 75
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
IS - 1
ER -