Low‐dose methotrexate (MTX) inhibits methionine S‐adenosyltransferase (MAT) in vitro and in vivo

Abstract

MAT catalyzes the only reaction that produces the major methyl donor in mammals. Low‐dose MTX is a commonly used DMARD. We tested the hypothesis that MTX inhibits MAT in vitro and in vivo. HepG2 cells were cultured under folate restriction or low‐dose MTX with and without folate or methionine supplementation. Mice received MTX regimens that reflected low‐dose clinical use in humans. We found that methionine or folate supplementation greatly improved SAM in folate‐depleted cells but not in cells preexposed to MTX. MTX but not folate depletion suppressed MAT genes, proteins and activity. Low‐dose MTX inhibited MAT1A and MAT2A genes, MATI/II/III proteins and MAT enzyme activities in mouse tissues. Concurrent folinate supplementation with MTX ameliorated MAT2A reduction and restored SAM in cells. However, posttreatment folinate rescue failed to restore MAT reduction or SAM level in cells preexposed to MTX. We provide both in vitro and in vivo evidence that lowdose MTX inhibits MAT genes, proteins, and enzyme activity independent of folate depletion. Because polyglutamated MTX stays in the hepatocytes, if MTX inhibits MAT in the liver, the efficacy of clinical folinate rescue with respect to maintaining hepatic SAM would be limited. The study raise concerns on perturbed methylation reactions in humans on low‐dose MTX. Well‐designed trials for optimizing SAM and methylation status in patients taking MTX are warrantedGrant Funding Source: National Science Council

Quantum Heat Engine and Negative Boltzmann Temperature

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