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.