Choline deficiency and methotrexate treatment induces marked but reversible changes in hepatic folate concentrations, serum homocysteine and DNA methylation rates in rats. 1995

G Varela-Moreiras, and C Ragel, and J Pérez de Miguelsanz
Departamento de Nutrición I, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.

OBJECTIVE The study compared the effects of feeding rats a choline deficient (CD) diet or injecting low doses of methotrexate (MTX) on hepatic folate concentration and distribution, homocysteine (Hcy) concentration and DNA methylation. METHODS Thirty rats were divided into three groups and were fed either a choline sufficient (CS) or deficient diet (CD), or injected with low doses of MTX (0.1 mg/kg/day) for 2 weeks. Half the animals of each group were sacrificed and the remaining CD and MTX animals were fed repletion diets without methotrexate administration for two additional weeks. RESULTS CD or MTX resulted in a significantly lower folate concentrations (25-50%) compared to the control group. Folate distribution in the treated animals was associated with elongation of the glutamate chains: higher proportion of hexa (from 14%, control, to 35%, choline, p < 0.05), hepta (from 5% to 16%, p < 0.05), and appearance of octaglutamyl folates. MTX administration resulted in a similar pattern of hepatic folate distribution. Two weeks following the MTX administration and the restoration of an adequate choline diet for 2 weeks restored the hepatic folate levels to the control animals. CONCLUSIONS Results are discussed based on the possibility that CD and MTX treatment appear to impair the capacity of tissues to incorporate folate in only 2 weeks and affect other biomarkers of one-carbon metabolism such as Hcy concentration and DNA methylation. This adverse picture was partially reversed in a relative short time by simply feeding an adequate CS diet and discontinuing MTX injections.

UI MeSH Term Description Entries
D008099 Liver A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances. Livers
D008297 Male Males
D008727 Methotrexate An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of TETRAHYDROFOLATE DEHYDROGENASE and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. Amethopterin,Methotrexate Hydrate,Methotrexate Sodium,Methotrexate, (D)-Isomer,Methotrexate, (DL)-Isomer,Methotrexate, Dicesium Salt,Methotrexate, Disodium Salt,Methotrexate, Sodium Salt,Mexate,Dicesium Salt Methotrexate,Hydrate, Methotrexate,Sodium, Methotrexate
D008745 Methylation Addition of methyl groups. In histo-chemistry methylation is used to esterify carboxyl groups and remove sulfate groups by treating tissue sections with hot methanol in the presence of hydrochloric acid. (From Stedman, 25th ed) Methylations
D002794 Choline A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism. Bursine,Fagine,Vidine,2-Hydroxy-N,N,N-trimethylethanaminium,Choline Bitartrate,Choline Chloride,Choline Citrate,Choline Hydroxide,Choline O-Sulfate,Bitartrate, Choline,Chloride, Choline,Choline O Sulfate,Citrate, Choline,Hydroxide, Choline,O-Sulfate, Choline
D002796 Choline Deficiency A condition produced by a deficiency of CHOLINE in animals. Choline is known as a lipotropic agent because it has been shown to promote the transport of excess fat from the liver under certain conditions in laboratory animals. Combined deficiency of choline (included in the B vitamin complex) and all other methyl group donors causes liver cirrhosis in some animals. Unlike compounds normally considered as vitamins, choline does not serve as a cofactor in enzymatic reactions. (From Saunders Dictionary & Encyclopedia of Laboratory Medicine and Technology, 1984) Deficiency, Choline,Choline Deficiencies,Deficiencies, Choline
D005492 Folic Acid A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses (POACEAE). Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. Pteroylglutamic Acid,Vitamin M,Folacin,Folate,Folic Acid, (D)-Isomer,Folic Acid, (DL)-Isomer,Folic Acid, Calcium Salt (1:1),Folic Acid, Monopotassium Salt,Folic Acid, Monosodium Salt,Folic Acid, Potassium Salt,Folic Acid, Sodium Salt,Folvite,Vitamin B9,B9, Vitamin
D005493 Folic Acid Antagonists Inhibitors of the enzyme, dihydrofolate reductase (TETRAHYDROFOLATE DEHYDROGENASE), which converts dihydrofolate (FH2) to tetrahydrofolate (FH4). They are frequently used in cancer chemotherapy. (From AMA, Drug Evaluations Annual, 1994, p2033) Antifolate,Antifolates,Dihydrofolate Reductase Inhibitor,Folic Acid Antagonist,Dihydrofolate Reductase Inhibitors,Folic Acid Metabolism Inhibitors,Acid Antagonist, Folic,Acid Antagonists, Folic,Antagonist, Folic Acid,Antagonists, Folic Acid,Inhibitor, Dihydrofolate Reductase,Inhibitors, Dihydrofolate Reductase,Reductase Inhibitor, Dihydrofolate,Reductase Inhibitors, Dihydrofolate
D006710 Homocysteine A thiol-containing amino acid formed by a demethylation of METHIONINE. 2-amino-4-mercaptobutyric acid,Homocysteine, L-Isomer,2 amino 4 mercaptobutyric acid,Homocysteine, L Isomer,L-Isomer Homocysteine
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

Related Publications

G Varela-Moreiras, and C Ragel, and J Pérez de Miguelsanz
January 1991, Cancer research,
G Varela-Moreiras, and C Ragel, and J Pérez de Miguelsanz
August 1991, The Journal of nutrition,
G Varela-Moreiras, and C Ragel, and J Pérez de Miguelsanz
July 2006, Metabolism: clinical and experimental,
G Varela-Moreiras, and C Ragel, and J Pérez de Miguelsanz
January 2010, Cancer prevention research (Philadelphia, Pa.),
G Varela-Moreiras, and C Ragel, and J Pérez de Miguelsanz
March 2009, The Journal of nutritional biochemistry,
G Varela-Moreiras, and C Ragel, and J Pérez de Miguelsanz
May 2002, Toxicological sciences : an official journal of the Society of Toxicology,
G Varela-Moreiras, and C Ragel, and J Pérez de Miguelsanz
February 2008, Proceedings of the National Academy of Sciences of the United States of America,
G Varela-Moreiras, and C Ragel, and J Pérez de Miguelsanz
October 2007, DNA and cell biology,
G Varela-Moreiras, and C Ragel, and J Pérez de Miguelsanz
October 2013, Nutrition (Burbank, Los Angeles County, Calif.),
Copied contents to your clipboard!