Deficiency of glycine N-methyltransferase results in deterioration of cellular defense to stress in mouse liver.
OBJECTIVE
Previously, we reported that glycine N-methyltransferase (GNMT) interacts with benzo[a]pyrene (BaP) and inhibits BaP-DNA adducts formation. In addition, Gnmt knockout (Gnmt(-/-)) mice developed chronic hepatitis and hepatocellular carcinoma (HCC). The aims of this study were to understand the gene expression profile of Gnmt(-/-) mice and to study the interaction between BaP and GNMT deficiency in vivo.


METHODS
Gene expression profiles of Gnmt(-/-) mice were analyzed by 2-D PAGE and real-time PCR. Both wild-type and Gnmt(-/-) mice were challenged with BaP and sacrificed at the age of 13 months.


RESULTS
Compared with the wild-type mice, proteins involved in the anti-oxidation/detoxification response, glycolytic energy metabolism and one-carbon metabolism pathways were down-regulated significantly in Gnmt(-/-) mice. Malondialdehyde assay showed that lipid peroxidation was significantly increased in the Gnmt(-/-) mice liver. H(2)O(2) treatment demonstrated that the survival rate of HuH-7 cells overexpressing GNMT was significantly higher than the controls. BaP challenge experiments showed that 71.4% (5/7) of male and all (7/7) female Gnmt(-/-) mice developed HCC, while only 16.7% (1/6) of male and 20% (1/5) of female wild-type mice had HCC.


CONCLUSIONS
GNMT regulates genes related to detoxification and anti-oxidation pathways. BaP is a liver cancer carcinogen especially during GNMT deficiency.
Molecular Medicine Program, Institute of Public Health, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Yi-Jen
YJ
Liao
Kuan-Hsuan
KH
Chen
Shiu-Feng
SF
Huang
Tzu-Lang
TL
Chen
Chung-Kwe
CK
Wang
Chau-Heng
CH
Chien
Ting-Fen
TF
Tsai
Shih-Ping
SP
Liu
Yi-Ming Arthur
YM
Chen
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000503:physiopathology; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D050938:Glycine N-Methyltransferase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006505:Hepatitis / Q000235:genetics / Q000503:physiopathology; D015227:Lipid Peroxidation; D008099:Liver / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D040081:Protein Array Analysis; D040901:Proteomics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological
D050938:Glycine N-Methyltransferase