Mechanisms of hepatotoxicity caused by dacarbazine in rats.
Possible risks of fatal dacarbazine hepatotoxicity have not been studied systematically. We therefore asked whether dacarbazine hepatotoxicity is influenced by the dose or mode of application, by dacarbazine light-decay products, by prior liver damage or by an induction of dacarbazine metabolism. 22 Sprague-Dawley rats were treated with 4.5 mg and 200 mg dacarbazine/kg bodyweight i.p. and i.v., with dacarbazine light-decay products and with 4.5 mg and 200 mg dacarbazine/kg bodymass after previous galactosamine and ethanol treatment. Serum alanine aminotransferase, cholinesterase and white blood cell and platelet numbers were measured and liver histology was evaluated. Dose-dependent dacarbazine hepatotoxicity could be demonstrated by histology. The mode of application, dacarbazine light-decay products and acute liver damage did not influence dacarbazine hepatotoxicity. However 200 mg dacarbazine/kg bodymass after ethanol pretreatment caused significant serological changes and a significant leucodepression. The increased hepato- and myelotoxicity after induction of hepatic microsomal enzymes should be reason to exclude ethanol and drugs that induce hepatic microsomal enzymes prior to treatment with dacarbazine.
II. Medical Clinic, Klinikum Mannheim, Universität Heidelberg, Germany.
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R
Paschke
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M
Heine
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S
Braun
K H
KH
Usadel
D000410:Alanine Transaminase / Q000187:drug effects; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury; D002802:Cholinesterases / Q000187:drug effects; D003606:Dacarbazine / Q000633:toxicity*; D004790:Enzyme Induction; D007962:Leukocytes / Q000187:drug effects; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000201:enzymology / Q000473:pathology; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley
D003606:Dacarbazine; D000410:Alanine Transaminase; D002802:Cholinesterases