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

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Abstract
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. 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. 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. 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.