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Department of Pharmacology
Alexander Steven Whitehead, D.Phil.

Education:

1977	B.Sc.	Edinburgh University
1982	D.Phil.	Oxford University

Research Summary:
The role of genetic variants of enzymes of folate/homocysteine metabolism in human disease. Folate is an essential vitamin that participates in many biochemical reactions that are important for a number of key biological processes. These include the methylation of substrates such as DNA, proteins and drugs, and the synthesis of purines and pyrimidines. Inadequate intake of folate or altered proportional distribution of the various intracellular forms of folate, together with elevated levels of the amino acid homocysteine, which requires folate to be methylated to methionine, have been associated with many major human pathologies ranging from neural tube defects (NTDs) to cardiovascular disease. For most such pathologies it is unclear whether it is inadequate folate or high homocysteine that is the pathogenic agent.

We are studying the effect of functional polymorphisms of the enzymes that control folate/homocysteine metabolism to determine their impact on folate/homocysteine phenotype. Candidate functional polymorphisms are further investigated to establish whether they are associated with increased risk of disease or poor pregnancy outcome. To date we have identified several genetic risk factors (e.g. MTHFR, MTR, MTRR, TYMS, DHFR, NOS3, NAT1, CCL-2) that are significantly associated with one or more clinical conditions (e.g. NTD, cardiovascular disease, systemic lupus erythematosis, hyperhomocysteinemia).

Several widely used drugs specifically target enzymes in the folate/homocysteine metabolic pathway. For example methotrexate (MTX) inhibits dihydrofolate reductase (DHFR) and 5-fluoro-uracil (5-FU) inhibits thymidylate synthase (TYMS). We are monitoring changes in the folate/homocysteine phenotype of genotyped patients being treated with MTX for arthritic diseases and with 5-FU for cancer to establish whether there are biomarkers or genetic markers that predict drug toxicity and/or efficacy. The identification and validation in future clinical trials of such markers of drug action could facilitate the advent of pharmacogenetic tests that would be used to guide therapy for patients who need to be treated with anti-inflammatory and chemotherapeutic agents.

Recently we have developed a cell culture model of low folate stress in order to investigate the changes in cell morphology, proliferation, and gene expression that are elicited by the perturbations in folate/homocysteine metabolism that are elicited by genetic, nutritional and pharmacologic variables. We have already established that cells grown under low folate conditions respond by synthesizing and exporting pro-inflammatory signal molecules including monocyte chemo-attractant protein-1(MCP-1). A functional polymorphism of MCP-1 has consequently been assessed for its relationship to pathologies associated with a low folate/high homocysteine phenotype, and found to be a maternal risk factor for spina bifida, a common NTD. This work has the potential to identify products that are involved in disease pathogenesis and that may have functional polymorphisms that promote disease and/or alter drug responses.