title: Methotrexate accumulation and folate depletion in cells as a possible mechanism of chronic toxicity to the drug.
abstract: Methotrexate has been associated with chronic toxicities such as cirrhosis and neurological impairments ranging from mild learning disorders to a fatal leucoencephalopathy. The mechanism(s) for this toxicity is not completely understood. Certain tissues can convert methotrexate to polyglutamates. This results in a more persistent intracellular form of the drug. In this study the intracellular levels of folate and methotrexate were measured in the erythrocytes and liver of patients treated chronically with methotrexate. These tissues showed an accumulation of methotrexate as polyglutamates and a concomitant loss of folate. Folate concentrations were below normal in nine of 12 red cell and three of five liver samples. It is proposed that persistent methotrexate concentrations and/or the associated folate deficiency may be related to the toxicity of methotrexate, especially in time of cellular stress.
mesh_terms: D004912:Erythrocytes / Q000378:metabolism; D005492:Folic Acid / Q000378:metabolism*; D005494:Folic Acid Deficiency / Q000139:chemically induced; D007945:Leukemia, Lymphoid / Q000188:drug therapy / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008727:Methotrexate / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000378:metabolism; D011099:Polyglutamic Acid / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D005492:Folic Acid; D008727:Methotrexate