Date of Award

Fall 2011

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Pharmacology

First Advisor

Alexander S. Whitehead

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 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 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.

Included in

Pharmacology Commons

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