Choline antagonism of methotrexate liver toxicity in the rat

Abstract

Because of the frequent reports of hepatic toxicity associated with long-term administration of methotrexate, a rat model was developed utilizing daily methotrexate administration. This model revealed an incidence of fatty metamorphosis of over 80 percent, atrophy and necrosis of 30 percent, and fibrosis of 10 percent. Fatty liver changes did not differ substantially from control animals in those animals receiving long-term thydroxyurea, an agent which, like methotrexate, inhibits DNA synthesis but unlike methotrexate, does not impair methylation reactions. Because choline has a lipotropic effect and because its synthesis requires methylation, an attempt was made to block the liver toxicity of methotrexate by simultaneous administration of choline. Animals so treated did not show the pathologic changes in the liver characteristic of methotrexate treatment alone. Furthermore, the accumulation of triglycerides in the liver which was characteristic of methotrexate administration was markedly reduced in those animals receiving choline. These data strongly suggest that, in the rat model, methotrexate produced liver toxicity by virtue of an effect other than inhibition of DNA synthesis; and that this toxicity can be blocked without impairing methotrexate effect on bone marrow by the administration of choline, a lipotropic agent requiring methylation for its synthesis. It is suggested that these results may have implications for human therapeutic situations involving long-term administration of methotrexate.

Evaluation of the Chronic Hepatic Toxicity of 6-Mercaptopurine in the Wistar Rat

“…This finding was in marked contrast to the effect of chronic MTX administration on the hepatic triglyceride content [8,9]. In the present experiment, the chronic administration of 6-MP produced a significant decrease in the hepatic content of triglycerides, and this effect was apparently antagonized by C administration.…”

“…In experimental animals, cirrhosis can be induced by a C-deficient diet [6,7]. It has been shown that C can prevent the morphologic and biochemical damage caused by MTX administration in an experimental system suggesting that C deficiency may contribute to the hepatic toxicity of MTX [8,9], 6-MP is metabolized into compounds which both impair the de novo synthesis of purines and interfere with purine interconversion [10]. Theoretically, the hepatic toxicity observed with this drug could also be secondary to C depletion.…”

The fetal origins of memory: The role of dietary choline in optimal brain development

“…15 Choline supplementation reverses the fatty liver caused by methotrexate administration. [16][17][18] Thus, methionine, methyltetrahydrofolate, and choline are fungible sources of methyl groups. The fact that several parallel pathways exist to help ensure an adequate supply of methyl donors demonstrates the physiological importance of these compounds.…”

Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans

“…Rats treated with methotrexate have diminished pools of all choline metabolites in liver (21). Choline supplementation reverses the fatty liver caused by methotrexate administration (22)(23)(24). Genetically modified mice with defective 5,10-methylene tetrahydrofolate reductase (MTHFR) activity become choline-deficient (25), an important observation because many humans have genetic polymorphisms that alter the activity of this enzyme (26,27).…”