title: Impairment of energy metabolism in cardiomyocytes caused by 5-FU catabolites can be compensated by administration of amino acids.
abstract: Identification of patients with increased risk of 5-fluorouracil (5-FU)-related toxicity is an important challenge for cancer treatment. Research often focus on dihydropyrimidine dehydrogenase (DPYD) deficiency in this context. However, patients with normal DPYD activity may also develop life-threatening 5-FU adverse effects. DPYD initiates the catabolic route of 5-FU generating metabolites such as fluoroacetate (FAC). The catabolite FAC is known to inhibit the TCA cycle enzyme aconitase, which is supposed to impair mitochondrial energy metabolism. Therefore, we aim for a systems understanding of the association of 5-FU-related cardiac side effects with aconitase inhibition caused by FAC. Using a mitochondrial model of cardiomyocytes we found strong depletion of ATP production and citrate accumulation as main effects of aconitase inhibition. Shadow price analysis revealed that the uptakes of valine, arginine, proline and glutamate are most effective in compensating the impairment of energy metabolism. Our findings suggest that 5-FU catabolism contributes to the occurrence of cardiac adverse effects and are the basis for further biomarker identifications and development of side effect treatment.
authors.forename: Julia
authors.initials: J
authors.lastname: Lischke
authors.forename: Christine
authors.initials: C
authors.lastname: Lang
authors.forename: Oliver
authors.initials: O
authors.lastname: Sawodny
authors.forename: Ronny
authors.initials: R
authors.lastname: Feuer
mesh_terms: D000154:Aconitate Hydratase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000596:Amino Acids / Q000008:administration & dosage* / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects*; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism
chemical_list: D000596:Amino Acids; D000255:Adenosine Triphosphate; D000154:Aconitate Hydratase; D010100:Oxygen; D005472:Fluorouracil