Hepatotoxicity in Wistar Rats Following Chronic Methotrexate Administration: A Model of Human Reaction2

Abstract

The effects of ip administration of methotrexate (MTX) on 3-month-old male Wistar rats were studied. We administered log doses from 125 to 2,000 mug/kg, five times per week for as long as 24 months. The massive doses were promptly lethal, and most rats receiving 500 mug or more/kg died within a few weeks. Severe hematopolietic depression and ulcerative gastrointestinal lesions were observed. Truly chronic intoxication was achieved with the lesser doses. Rats in this category developed serious liver damage, namely, varying degrees of fatty metamorphosis, necrosis, atrophy of hepatic cords, and fibrosis. Hematopoietic depletion occurred in the spleen and bone marrow. Hemosiderosis was prominent in the spleen and liver. Pulmonary lesions--chiefly emphysema, occasionally fibrosis--were found less consistently. These studies demonstrated the ability of MTX to induce lesions, most consistently hepatic, in the Wistar rat, and thus have provided an animal model to evaluate protective measures.

Hepatic Collagen Production in the Rat Is Unaffected by Methotrexate

“…As expected, measurement of hepatic t iglyceride did reveal a significant elevation in the MTX-treated animals (7.9 t-3.1 vs 4.8 -t 1.0 mg triglyceride/g liver, P < 0.05), confirming past observations of this MTX effect (15,16).…”

“…Custer et al ( 15) administered varying doses of MTX to rats for periods of up to 24 months and found fatty infiltration of the liver as well as a significant increase in hepatic triglyceride content when compared to control animals. These workers also noted that an unspecified number of rats given MTX had hepatic fibrosis, although the authors felt that this usually was due to "collapse."…”

“…Animals weighing approximately 80 g received one of four experimental regimens: (i) control-normal saline (volume equal to that of Group iii) ip qd ("qd" defined as 5 consecutive days per week); (ii) MTX, 250 pg/kg ip qd; (iii) MTX, 400 pg/kg ip qd; (iv) MTX, 600 pg/kg ip qod ("qod" defined as every other day). Dosages were chosen in an attempt to induce maximal hepatotoxicity without mortality in the first 2 months of drug administration based on the data of Custer et al ( 15). MTX-induced hepatotoxicity, as measured by hepatic triglyceride content, has been shown to be dose-dependent and reproducible (15,16).…”

“…Dosages were chosen in an attempt to induce maximal hepatotoxicity without mortality in the first 2 months of drug administration based on the data of Custer et al ( 15). MTX-induced hepatotoxicity, as measured by hepatic triglyceride content, has been shown to be dose-dependent and reproducible (15,16). Animals were weighed each week and doses adjusted accordingly.…”

Enzyme-Linked Immunosorbent Assay for Serum Procollagen Type III Peptide in Rats with Hepatic Fibrosis.

“…Concerning the methods to induce animal models for hepatic fibrosis, there are many animal reports [2,5,7,16,17]. In this study, we chose two models characterized by marked hepatic fibrosis with no prominent inflammation served as controls and 6 rats each were killed in the same way.…”