Toxicogenomic studies reveal biosynthetic pathway of S-adenosylmethione as a possible hepatotoxic mechanism
M. Chen1, L.K. Schnackenberg2, L. Guo2, R. Holland2, R.D. Beger2, Q. Shi2, S. Isukapalli1, P.G. Georgopoulos1, W. Welsh1, W. Tong2
1ebCTC,UMDNJ-RWJMS; 2USFDA-NCTR
DNA microarrays and metabonomics can be used to investigate and better understand the biological processes involved in disease and toxicity through an integrated analysis of gene expression and metabolic networks. In a previous study using a NMR-based metabonomic approach to examine mechanisms involved in liver toxicity, we identified N-methylnicotinate as a potential liver toxicity biomarker. Since biochemical formation of N-methylnicotinate resulted from transferring a methyl group from S-adenosylmethione (AdoMet) to nicotinamide, we hypothesize that the urinary levels of N-methylnicotinate in rat urine samples could be an indicator of the AdoMet levels in liver tissue. In this study, two independent public gene expression datasets from the Gene Expression Omnibus (GEO) database were used to further examine the effect of liver toxicants on the AdoMet biosynthesis pathway related to the production of glutathione. In both studies, two genes (BHMT and Mat1a) involved in biosynthesis of AdoMet were found significantly decreased in the toxic samples compared with the non-toxic or control samples. The results are inconsistent with the findings from our previous metabonomic study whereas the AdoMet biosynthesis pathway involved in glutathione production is affected by known liver toxicants. Thus, our study demonstrated that urinary level of N-methylnicotinate related to the biosynthetic pathway of AdoMet may serve as a noninvasive biomarker of liver toxicity.
Support for this work has been provided primarily by the USEPA-funded Environmental Bioinformatics and Computational Toxicology Center (ebCTC), under STAR Grant number GAD R 832721-010. This work has not been reviewed by and does not represent the opinions of the funding agency.