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. H₂O₂ 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 antioxidation pathways. BaP is a liver cancer carcinogen especially during GNMT deficiency.