Deficiency of glycine N ‐methyltransferase results in deterioration of cellular defense to stress in mouse liver

Purpose : 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 . Experimental design : 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. Conclusion and clinical relevance : GNMT regulates genes related to detoxification and anti‐oxidation pathways. BaP is a liver cancer carcinogen especially during GNMT deficiency.