Chronic Toxicity of Methotrexate in Rats: Partial to Complete Protection of the Liver by Choline: Brief Communication23

Abstract

Methotrexate (MTX) inhibits the enzyme dihydrofolate reductase, which in turn limits the body's ability to perform transmethylation reactions. This study examined the hypothesis that the consequent deficiency of an important methylated compound, choline, may have contributed to the MTX-induced fatty change in the liver of W rats. Groups of rats were given MTX alone or MTX plus choline in varying dose combinations. All groups but one receiving the combined treatment showed a significantly lower triglyceride concentration in their livers and much less visible hepatocytic fat on histologic examination than did those given MTX alone. The protective effect of choline on the liver was dose related, the unaffected group having received a very small amount. Growth rate, survival, and hematopoietic depression due to MTX were unaltered by choline administration.

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.…”

“…Such an effect was reported previously following the chronic administra tion of MTX [8]. In acute toxicity experiments with 6-MP, rats were noted to lose weight, but death generally occurred within 24-48 h [19].…”

“…This was an unexpected finding because previous authors did not include experimental groups treated with C only [8]. It has been noted by others that the administration of C as an oral 2 or 4% solution was associated with impaired water consumption and poor weight gain [8].…”

“…1A). The doses of C employed were 70 and 140 mg/kg, based on previous work [8], At the higher dose, 30% of the animals died before the completion of the experiment ( fig. IB).…”

“…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.…”