Hepatotoxicity in a rat model caused by orally administered methotrexate

Abstract

We undertook a dose-response study in Wistar rats to develop an animal model for methotrexate hepatotoxicity. Rats were given oral methotrexate in 300, 200, 150 and 100 micrograms/kg/day doses for variable lengths of time. The 300 micrograms/kg/day dose produced systemic toxicity; the animals needed to be killed early, and hepatotoxicity was not observed. The lower doses of methotrexate were tolerated for longer durations and were associated with hepatotoxicity in five of the five rats receiving 200 micrograms/kg/day, four of the five rats receiving 150 micrograms/kg/day and five of the five rats on 100 micrograms/kg/day. Within each treatment group the liver injury ranged in severity from focal necrosis of some zone 3 hepatocytes to confluent necrosis of zone 3. All five rats that received 100 micrograms/kg/day methotrexate for 6 wk showed continuing liver injury in the form of focal necrosis, cell lysis and enlarged Kupffer cells. In addition, three of the rats showed evidence of early hepatic fibrosis. We believe that this is the first experimental model in which oral methotrexate administration has been associated with hepatotoxicity. Further development of this model should provide valuable insights into the pathogenesis of methotrexate hepatotoxicity.

The effect of active hexose correlated compound in modulating cytosine arabinoside-induced hair loss, and 6-mercaptopurine- and methotrexate-induced liver injury in rodents

“…The benefits for the inclusion of AHCC in chemotherapy strategy can allow the setting of the effective dosage in clinical practice [48], a view that is consistent with the interest in the economics of chemotherapy [3,4,59,60]. Further, the combination of high-dose MTX with intravenous mercaptopurine is superior to low-dose MTX with mercaptopurine [61][62][63], but it remains equivocal that high-dose MTX produces greater enhancement of thiopurine intracellular accumulation compared with low-dose MTX [22,64]. Mack et al [65] found that low-dose, weekly and subcutaneous MTX administration can induce remission in some pediatric patients with Crohn's disease who fail to adequately respond to other immunomodulator medications.…”

Role of Ursodeoxycholic Acid in Prevention of Methotrexate-induced Liver Toxicity

“…In our study, a single dose of 20 mg/kg MTX was used to induce toxic effects on the liver tissue since higher doses of the drug might have resulted in severe systemic toxicity and early death of animals from other reasons such as acute gastrointestinal injury and bone marrow toxicity. As a result, histopathologically MTX toxicity was determined by focal necrosis areas and multiple hepatocyte loss [38]. This dose, which allowed the animals to survive MTX toxicity, also enabled us to witness the preventive effect of UDCA on MTX injury.…”

L-Carnitine ameliorates methotrexate-induced oxidative organ injury and inhibits leukocyte death

“…This malabsorption results in weight loss and disturbs the cancer chemotherapy of patients. Additionally, cyclical high doses of MTX, as used for acute leukemia (Hersh et al, 1966;Hall et al, 1991), or the relatively high doses of MTX used to treat severe psoriasis, have been associated with liver hepatotoxicity, including progressive hepatic fibrosis and cirrhosis (Roenigk et al, 1971;Tobias and Auerbach, 1973). Furthermore, MTX can cause increased serum creatinine levels, uremia and hematuria, while its administration in high doses has been reported to cause acute renal failure (Kintzel, 2001).…”