Ethylene dibromide and disulfiram: studies in vivo and in vitro on the mechanism of the observed synergistic carcinogenic response.
Two possible mechanisms for the reported carcinogenic synergism between ethylene dibromide (EDB) and disulfiram have been investigated in vivo and in vitro, the first involving increased production of an EDB-derived glutathione mustard and the second increased production of bromoacetaldehyde. Consistent with both of these suggested mechanisms, repeated administrations of disulfiram to rats inreased liver glutathione-S-transferase activity and decreased liver low Km aldehyde dehydrogenase activity. However, when added to a rat liver S-9 fraction in vitro, disulfiram decreased transferase activity and only depressed the dehydrogenase activity after a period of preincubation. Although the mutagenic potency of EDB to Salmonella typhimurium was slightly enhanced in vitro by the addition of a rat liver S-9 fraction, the further addition of disulfiram to the assay medium produced no additional change. Similarly, the addition of a range of S-9 and S-0.5 liver fractions derived from disulfiram-treated rats also failed to enhance significantly its mutagenic potency over the normal S-9 fraction. The general implications of these findings are discussed.
Imperial Chemical Industries Limited, Central Toxicology Laboratory, Macclesfield, Cheshire, UK.
B M
BM
Elliott
J
J
Ashby
D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors; D000477:Alkylating Agents / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D001140:Aroclors / Q000494:pharmacology / Q000633:toxicity; D001711:Biotransformation / Q000187:drug effects; D002273:Carcinogens / Q000494:pharmacology / Q000633:toxicity*; D003043:Cocarcinogenesis; D004221:Disulfiram / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D015946:Ethylene Dibromide / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D005798:Genes, Bacterial / Q000187:drug effects; D005978:Glutathione / Q000031:analogs & derivatives / Q000096:biosynthesis; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D009153:Mutagens / Q000494:pharmacology / Q000633:toxicity; D011355:Prodrugs / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012486:Salmonella typhimurium / Q000187:drug effects
D000477:Alkylating Agents; D001140:Aroclors; D002273:Carcinogens; D004791:Enzyme Inhibitors; D009153:Mutagens; D011355:Prodrugs; C422750:glutathione mustard; C038235:bromoacetaldehyde; D015946:Ethylene Dibromide; D000444:Aldehyde Dehydrogenase; D005982:Glutathione Transferase; D005978:Glutathione; D000079:Acetaldehyde; D004221:Disulfiram