Journal Article

Methotrexate alters carbon flow through the hepatic folate-dependent one-carbon pool in rats

Kevin L. Schalinske and Robert D. Steele

in Carcinogenesis

Volume 17, issue 8, pages 1695-1700
Published in print August 1996 | ISSN: 0143-3334
e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/17.8.1695
Methotrexate alters carbon flow through the hepatic folate-dependent one-carbon pool in rats

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The chemotherapeutic value of methotrexate resides in its ability to perturb folate-dependent one-carbon metabolism and subsequently inhibit DNA synthesis. To assess the functional effect of methotrexate on hepatic one-carbon metabolism, we have developed and applied tracer kinetic techniques in vivo to quantify the carbon flux through the folate-dependent one-carbon pool in rats. Following a 7-day treatment period with methotrexate (0.2 mg/kg body weight), the tracers L-[ring-2-l4C] histidine and L-[methyl-3H] methionine were simultaneously infused into control and methotrexate-treated rats. Methotrexate treatment decreased hepatic tetrahydrofolate, methyltetrahydrofol-ate, and formyltetrahydrofolate concentrations by 63, 83, and 58%, respectively. Furthermore, the enzymatic activity of 10-formyltetrahydrofolate dehydrogenase, the terminal enzyme in the catabolism of the ring-2-carbon of histidine to CO2, was diminished by 32% in methotrexate-treated animals. These changes in enzyme activity and folate coenzyme concentrations did not result in a significant decrease in the oxidative flow of carbon from histidine to CO2 in methotrexate-treated rats compared to control animals (2.40 and 3.22 (imol/h/kg3/4, respectively). Oxidative carbon flow was reflective of tetrahydrofolate and formyltetrahydrofolate pools when expressed as a percent of total folate: neither coenzyme pool was diminished as a result of methotrexate treatment In contrast, the reductive carbon flux through the one-carbon pool from histidine to methionine was significantly decreased 59% in methotrexate-treated (7.63 μmol/h/kg¾) versus control rats (18.73 nmolAh/kg3/4)). Likewise, methyltetrahydrofolate, as a percent of total folate, was reduced 51% in methotrexate-treated rats. Consequently, total measured carbon flow (oxidative + reductive) was 54% lower in rats subjected to subchronic methotrexate treatment These tracer kinetic experiments quantitatively demonstrate the extent to which methotrexate alters the actual carbon flow through the hepatic folate-dependent one-carbon pool, primarily directed at diminishing the reductive carbon flow towards methyltetrahydrofolate and methionine synthesis.

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Subjects: Clinical Cytogenetics and Molecular Genetics

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