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.

Male Fischer 344 rats were exposed to halothane, enflurane or isoflurane vapour 20 p.p.m., or air, for up to 30 weeks. None of the anaesthetic agents led to hepatocellular necrosis. Exposure to halothane resulted in slight increases in serum alanine aminotransferase activity, an increase in the size of the liver, an increase in hepatic microsomal cytochrome P-450 content and a minimal amount of fatty change in the liver. None of these effects were observed during exposure to enflurane or isoflurane. Urinary fluoride excretion was increased during exposure to either enflurane or isoflurane. Using this increase as an index of anaesthetic biotransformation, we found that the extent of biotransformation of isoflurane was only slightly lower than that of enflurane.

We present here a patient with end stage renal failure who received two weeks antimalarial prophylaxis at full dose leading to life threatening toxicity with severe acute megaloblastic anaemia, symptomatic pancytopenia and exfoliative dermatitis. Prompt recognition and treatment can rapidly reverse these fatal effects but more importantly, education of patients before travel is imperative in preventing such events.

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Rats were exposed for four weeks either to air or to vapours of chloroform, carbon tetrachloride or 1,1-dichloroethylene given either as a constant concentration (continuous profile) or as repeated exposures for 6 hr per day, 5 days per week (fluctuating profile). Vapour concentrations were used such that the total exposure (concentration x time) was the same for the two profiles. Within each group, some animals received the enzyme-inducing agents, phenobarbitone or 1,3-butanediol, in their drinking water. Separate experiments were conducted to determine the influence of enzyme inducers and vapour concentration on chlorocarbon uptake and metabolism. In the case of chloroform, hepatic injury was more severe in animals exposed to constant vapour concentration, while dichloroethylene was more toxic when given as a fluctuating profile, especially in butanediol-treated rats. Carbon tetrachloride hepatotoxicity was similar in the two exposure profiles but was exacerbated by butanediol treatment. Butanediol-treated animals in the fluctuating profile group showed evidence of developing cirrhosis. These results could not be fully explained on the basis of the effect of enzyme inducers and exposure profile on amount of agent metabolized. Both the amount of toxic metabolites and the temporal pattern of their formation appear to be important determinants of liver injury.