Hepatocyte toxicity of mechlorethamine and other alkylating anticancer drugs. Role of lipid peroxidation.
The alkylating anticancer drugs, mechlorethamine (HN2), chlorambucil, cyclophosphamide, carmustine and lomustine readily induced cytotoxicity in isolated rat hepatocytes. Hepatocyte glutathione (GSH) was depleted rapidly following addition of the drugs. Lipid peroxidation ensued following GSH depletion and before cytotoxicity occurred. Furthermore, cytotoxicity was delayed by the antioxidants butylated hydroxyanisole (BHA) and alpha-tocopherol, the ferric iron chelator desferoxamine or the radical trap 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) even when added 10 min later. HN2 was much less toxic to hepatocytes under nitrogen and caused much less lipid peroxidation than under aerobic conditions. Cytotoxicity induced by HN2 was also prevented by choline, suggesting that a choline carrier is responsible for HN2 uptake in the hepatocytes. Various sulfur compounds acted as antidotes for HN2 cytotoxicity. Thiosulfate was still effective when added 30 min after HN2. Depletion of GSH in the hepatocytes markedly increased their susceptibility to HN2. However, BHA, desferoxamine or TEMPO protected these hepatocytes from HN2. This suggests that antioxidants could prove useful in preventing the increased risk of hepatotoxicity if GSH-depleting agents are used to overcome tumor resistance to nitrogen mustards.
Khan
S
S
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Ramwani
J J
JJ
O'Brien
P J
PJ
D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002083:Butylated Hydroxyanisole / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D008466:Mechlorethamine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D014810:Vitamin E / Q000494:pharmacology
D000477:Alkylating Agents; D000975:Antioxidants; D003497:Cyclic N-Oxides; D014810:Vitamin E; D002083:Butylated Hydroxyanisole; D008315:Malondialdehyde; D008466:Mechlorethamine; D005978:Glutathione; D003676:Deferoxamine; C003959:TEMPO