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Genetic Polymorphisms and Antifolate Drug Treatment Can Alter Folate/Homocysteine Metabolism and Inflammatory Protein Profile

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Genetic Polymorphisms and Antifolate Drug Treatment Can Alter Folate/Homocysteine Metabolism and Inflammatory Protein Profile University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations Fall 2011 Genetic Polymorphisms and Antifolate Drug Treatment Can Alter Folate/Homocysteine Metabolism and Inflammatory Protein Profile Andrea L. Hammons University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Pharmacology Commons Recommended Citation Hammons, Andrea L., "Genetic Polymorphisms and Antifolate Drug Treatment Can Alter Folate/ Homocysteine Metabolism and Inflammatory Protein Profile" (2011). Publicly Accessible Penn Dissertations. 965. https://repository.upenn.edu/edissertations/965 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/965 For more information, please contact [email protected]. Genetic Polymorphisms and Antifolate Drug Treatment Can Alter Folate/ Homocysteine Metabolism and Inflammatory Protein Profile Abstract The folate metabolic pathway is important in several biological processes, including purine and pyrimidine synthesis and the methylation of DNA and proteins. There are several pathologies that are associated with dysregulation of the folate/homocysteine (Hcy) metabolic pathway, including rheumatoid arthritis (RA), cardiovascular disease (CVD), and several cancers. Many of the pathologies associated with altered folate/Hcy metabolism have underlying inflammatory etiology. The distribution of folate derivatives can be influenced yb nutrient deficiency or insufficiency andy b genetic polymorphisms in important enzymes in the pathway. Additionally, antifolate drugs, such as methotrexate (MTX) and pemetrexed (PMX), modify folate/Hcy metabolism. The relationships between folate phenotype, genetic polymorphisms of folate pathway enzymes, and inflammatory proteins were examined in both population-based and cell culture studies. A study set of young adults was used to study these relationships in a healthy population. In females, MCP-1 concentrations were positively correlated with Hcy and negatively correlated with both serum and red blood cell folate; female MTHFR 677T carriers had particularly elevated MCP-1 concentrations. In an observational follow-up study of patients prescribed MTX, total folate concentration decreased and MCP-1 concentration increased between their initial (i.e. before starting MTX) and on-drug treatment visits. MTHFR 677C>T genotype was associated with changes in several of the clinical and biochemical variables examined. Additionally, changes in MCP-1 and IL-8 concentrations were positively correlated with one another. Treatment of EA.hy 926 endothelial cells with PMX caused a decrease in individual folate analytes in both cells adapted to growth in low folate conditions and folate-replete cells. Several genes were significantly up or down-regulated in PMX-treated Lo cells. Additionally, IL-8 and C3 protein concentrations were increased following PMX treatment in cells grown under low folate conditions. PMX drug treatment was shown in this study to have effects that lead to an increase in pro-inflammatory mediators in these folate- deplete cells. In a study of lung cancer patients and matched controls, the lung cancer cases had higher total red blood cell (RBC) folate and RBC 5-MTHF concentrations. Additionally, there were 38 MTHFR 677TT homozygotes in the cases, but only 24 controls had this genotype. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Pharmacology First Advisor Alexander S. Whitehead Keywords folate, homocysteine, MCP-1, inflammation Subject Categories Pharmacology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/965 GENETIC POLYMORPHISMS AND ANTIFOLATE DRUG TREATMENT CAN ALTER FOLATE/HOMOCYSTEINE METABOLISM AND INFLAMMATORY PROTEIN PROFILE Andrea L. Hammons A DISSERTATION in Pharmacology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2011 Supervisor of Dissertation Alexander S Whitehead, D. Phil. Professor of Pharmacology Graduate Group Chairperson Vladimir Muzykantov, MD/Ph.D. Professor of Pharmacology Dissertation Committee Ian Blair, Ph.D., Professor of Pharmacology Wenchao Song, Ph.D., Professor of Pharmacology Anil Vachani, MD, Assistant Professor of Medicine GENETIC POLYMORPHISMS AND ANTIFOLATE DRUG TREATMENT CAN ALTER FOLATE/HOMOCYSTEINE METABOLISM AND INFLAMMATORY PROTEIN PROFILE © 2011 Andrea L. Hammons ii DEDICATION This thesis is dedicated to my parents, Darrell and Barbara Hammons, for the sacrifices they’ve made to provide opportunities for me; to my brother, Mark Hammons, for being a supportive and understanding sibling, friend, and roommate; and to my grandparents, Fred and Merle Hammons and Joe and Florence Diasio, for always emphasizing the importance of education and encouraging me to take advantage of the opportunities that they never had. iii ACKNOWLEGEMENTS First and foremost, I would like to thank my advisor, Steve Whitehead, for his guidance and support during the several years that I have spent working in his lab. I owe particular thanks to Andrew Cucchiara, who spent many hours outside of class teaching me statistical programming. Anna Stanislawska-Sachadyn, Liselotte Jensen, Zhi-Yong Lu, and Carolyn Summers, former members of the Whitehead lab, offered their support and advice. My research would not have been possible without collaborative efforts with Stefanie Khartulyari, Arnaldo Diaz, Suhong Zhang, Jasbir Arora and Megan Morales. I would also like to thank the Assoian lab for sharing equipment. I am thankful to the members of my thesis committee, Ian Blair, Anil Vachani, Wenchao Song and Joan Von Feldt, for their guidance through this process. I would like to thank many members of the University of Pennsylvania Department of Pharmacology, in particular Sarah Squire, Mary Scott, Lise Miller, Gail Vogel, Rosalyn Rucker, Camie Minieri and Bet Williams. I would also like to thank Dr. John Tobias from the Penn Bioinformatics Core for his help with the statistical analysis of the microarrays for the cell culture study. The Young Hearts study was supported by the National Institutes of Health, Grant numbers: R01AR47663, P20RR020741, ES0P3013508, and R01HD039195; the Pennsylvania Department of Health, Grant number: 4100038714; and the British Heart Foundation. The Rheumatoid Arthritis study was supported by National Institutes of Health grant AR47663. The cell culture studies were supported by the Pennsylvania Department of Health grant 4100038714. The lung cancer study was supported by the Pennsylvania Department of Health grant 4100038714. iv ABSTRACT Genetic Polymorphisms and Antifolate Drug Treatment Can Alter Folate/Homocysteine Metabolism and Inflammatory Protein Profile Andrea L. Hammons Supervisor: Alexander S. Whitehead, D. Phil. The folate metabolic pathway is important in several biological processes, including purine and pyrimidine synthesis and the methylation of DNA and proteins. There are several pathologies that are associated with dysregulation of the folate/homocysteine (Hcy) metabolic pathway, including rheumatoid arthritis (RA), cardiovascular disease (CVD), and several cancers. Many of the pathologies associated with altered folate/Hcy metabolism have underlying inflammatory etiology. The distribution of folate derivatives can be influenced by nutrient deficiency or insufficiency and by genetic polymorphisms in important enzymes in the pathway. Additionally, antifolate drugs, such as methotrexate (MTX) and pemetrexed (PMX), modify folate/Hcy metabolism. The relationships between folate phenotype, genetic polymorphisms of folate pathway enzymes, and inflammatory proteins were examined in both population-based and cell culture studies. A study set of young adults was used to study these relationships in a healthy population. In females, MCP-1 concentrations were positively correlated with Hcy and negatively correlated with both serum and red blood cell folate; female MTHFR v 677T carriers had particularly elevated MCP-1 concentrations. In an observational follow-up study of patients prescribed MTX, total folate concentration decreased and MCP-1 concentration increased between their initial (i.e. before starting MTX) and on- drug treatment visits. MTHFR 677C>T genotype was associated with changes in several of the clinical and biochemical variables examined. Additionally, changes in MCP-1 and IL-8 concentrations were positively correlated with one another. Treatment of EA.hy 926 endothelial cells with PMX caused a decrease in individual folate analytes in both cells adapted to growth in low folate conditions and folate-replete cells. Several genes were significantly up or down-regulated in PMX-treated Lo cells. Additionally, IL-8 and C3 protein concentrations were increased following PMX treatment in cells grown under low folate conditions. PMX drug treatment was shown in this study to have effects that lead to an increase in pro-inflammatory mediators in these folate-deplete cells. In a study of lung cancer patients and matched controls, the lung cancer cases had higher total red blood cell (RBC) folate and RBC 5-MTHF concentrations. Additionally, there were 38 MTHFR 677TT homozygotes in the cases, but only 24 controls had this genotype. vi TABLE OF CONTENTS DEDICATION.................................................................................................................. iii ACKNOWLEDGMENTS .............................................................................................
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