Folate, B12, and Inhibitors - Fitz Flashcards
What is the first symptom of a vitamin B12 or Folate deficiency?
Megaloblastic Anemia
What cell processes is folate a carbon donor to?
Thymidylate Synthesis
Purine Synthesis
Amino Acid Metabolism
Vitamin B12 is a cofactor in the generation of what?
Tetrahydrofolate (from methylTH4)
Methylmalonyl CoA to Succinyl CoA
What is one cause of primary resistance in low doses of folate inhibitors?
Reduced expression of the Reduced Folate Carrier (RFC)
How does Leucovorin function?
Allows normal cells with functional RFC to overcome the drug induced inhibition of dihydrofolate reductase
How does Trimethoprim-Sulfamethoxazole work?
Trimethoprim = folic acid inhibitor
Sulfamethoxazole = blocks dihydropteroate synthetase
=>Blocks Folate Synthesis pathway via bacterial dihydrofolate reductase
What laboratory finding is diagnostic of a Vitamin B12 Deficiency?
Homocysteine (converted to methionine via B12 catalysis)
How is leucovorin used in rescue therapy?
Replaces folate by being converted to TH4
What are the naturally occuring forms of Vitamin B12?
Adenosylcobalamin
Methylcobalamin
Where is Folate found?
green, leafy vegetables, dried beans, peas, sunflower seeds, citrus fruits, yeast, liver and kidney
Fortified Cereal Products
Where is Vitamin B12 found?
Animal products and fortified food
Where is Folate absorbed?
small intestine
Where is Vitamin B12 absorbed?
small intestine with acidic pH and intrinsic factor
How is folate taken up in the Reduced Folate Carrier?
High capacity
Low affinity
LV>folate>MTX
How is folate taken up in the Folate Receptor?
Low capacity
High affinity
Folate»_space;>MTX
Define Polygultamination
Addition of glutamine onto folate to keep folate inside of cells in order to increase affinity of TH4 for target enzymes
What two factors lead to differential sensitivity in cancer cells?
Over-expression of Folate Receptor in Choriocarcinoma
Better Polyglutamination
What are the leading contributors to folate deficiency?
Insufficient dietary intake High demand (pregnancy) Alcoholism Intestinal disease (celiac sprue) Inhibitors
What is the leading cause of Vitamin B12 deficiency?
Malabsorption due to Intrinsic Factor deficiency –> will cause folate deficiency by preventing access to stored TH4
