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ToxSci Advance Access published online on March 30, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm067
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The Contribution of Methotrexate Exposure and Host Factors on Transcriptional Variance in Human Liver

Glenn S. Belinsky1, Ann L. Parke2, Qihong Huang5, Kerry Blanchard5, Supriya Jayadev5, Raymond Stoll5, Marti Rothe3, Luke E.K. Achenie6, Rishi R. Gupta6, George Y. Wu4 and Daniel W. Rosenberg1

1 Center for Molecular Medicine 2 Department of Rheumatology 3 Department of Dermatology 4 Division of Gastroenterology and Hepatology, University of Connecticut Health Center, Farmington, Connecticut 5 Boehringer-Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 6 Department of Chemical Engineering, University of Connecticut, Storrs, Connecticut

Please address all correspondence concerning this manuscript to either: Daniel W. Rosenberg, PhD, 263 Farmington Avenue, Farmington, CT 06030-3101, rosenberg{at}nso2.uchc.edu, (860) 679-8704, FAX: (860) 679-7639 or George Y. Wu, MD, PhD, 263 Farmington Avenue, Farmington, CT 06030-1845, wu{at}nso.uchc.edu, (860) 679-3158, FAX: (860) 679-3159

Received December 21, 2006; revision received March 12, 2007; accepted March 14, 2007


  Abstract

Long-term administration of methotrexate (MTX) for management of chronic inflammatory diseases is associated with risk of liver damage. In this study, we examined the transcriptional profiles of livers from patients treated with MTX. The possibility that expression signatures correlate with grade of fibrosis or underlying rheumatic disease was evaluated. Twenty-seven patients taking MTX were accrued for this study. Ten non-MTX exposed normal liver specimens were used as controls. Global mRNA expression was assayed using oligonucleotide arrays. 205 genes were significantly altered in MTX-exposed livers. Six of these genes were validated by qPCR. Two genes, CLN8 and ANKH that map to chromosomal locations previously associated with rheumatoid arthritis, were found to be elevated in MTX exposed samples. Subsequent pathway analysis indicates that MTX exposure is associated with the following key alterations: 1) upregulation of lipid biosynthetic genes, consistent with MTX-induced steatosis, 2) downregulation of pro-inflammatory chemokines, consistent with the anti-inflammatory effects of MTX, and 3) elevation of complement pathway gene expression. Complement 5, shown earlier to be correlated with liver fibrosis in mice, was found to be elevated (2-fold) in MTX-exposed livers. In conclusion, we have found the expression of a number of genes associated with rheumatic disease and/or MTX exposure to be significantly different. Differences in complement expression provide rationale for future correlative studies between MTX-induced liver fibrosis and C5 alleles in order to identify patients with increased risk for fibrosis.

This work was supported by a generous grant from Boehringer-Ingelheim Pharmaceuticals, Inc and the Herman Lopata Chair in Hepatitis Research (GYW).


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