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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.
Insights
Methotrexate causes liver damage in rats by affecting methylation, not DNA synthesis. Simultaneous choline administration prevents this liver toxicity without reducing methotrexate's anti-cancer effects.
Area of Science:
- Hepatology
- Toxicology
- Pharmacology
Background:
- Long-term methotrexate use is linked to frequent hepatic toxicity.
- Methotrexate inhibits DNA synthesis and methylation reactions.
- Hydroxyurea inhibits DNA synthesis but not methylation, serving as a control.
Purpose of the Study:
- To investigate the mechanism of methotrexate-induced liver toxicity.
- To determine if choline can prevent methotrexate-induced liver toxicity.
- To explore the role of methylation in methotrexate's hepatotoxicity.
Main Methods:
- A rat model was established using daily methotrexate administration.
- Rats were treated with methotrexate alone, hydroxyurea, or methotrexate plus choline.
- Liver pathology, including fatty metamorphosis, atrophy, necrosis, and fibrosis, was assessed.
- Triglyceride accumulation in the liver was measured.
Main Results:
- Methotrexate treatment resulted in over 80% incidence of fatty liver, 30% atrophy/necrosis, and 10% fibrosis.
- Hydroxyurea did not cause significant fatty liver changes compared to controls.
- Simultaneous choline administration blocked methotrexate-induced liver pathology and reduced triglyceride accumulation.
Conclusions:
- Methotrexate-induced liver toxicity in rats is likely due to an effect beyond DNA synthesis inhibition, possibly related to methylation interference.
- Choline, a lipotropic agent requiring methylation, effectively prevents methotrexate hepatotoxicity without compromising its bone marrow effects.
- These findings suggest potential therapeutic strategies for mitigating methotrexate-induced liver damage in humans.