Effect of cyanamide on toxicity and glutathione depletion in rat hepatocyte cultures: differences between two dichloropropanol isomers.
The effect of aldehyde dehydrogenase inhibition by cyanamide pre-treatment in vitro on dichloropropanol-dependent toxicity and glutathione depletion was investigated in 24 h rat hepatocyte cultures. Cyanamide pre-treatment had no effect on nitrophenol hydroxylase, 7-methoxy-, 7-ethoxy- or 7-benzyloxyresorufin O-dealkylase activities in 24 h cultures from untreated rats, and had no effect on intracellular glutathione content in cultures from untreated rats, or in cultures from isoniazid-treated rats in which cytochrome P4502E1 (CYP2E1) is increased. In cultures from untreated animals the primary alcohol, 2,3-dichloropropanol, was not toxic and did not significantly deplete glutathione. Cyanamide pre-treatment however, potentiated both toxicity and glutathione depletion. Induction of CYP2E1 also potentiated the toxicity of 2,3-dichloropropanol, and in these cultures cyanamide pre-treatment significantly increased both toxicity and glutathione depletion. Cyanamide did not alter the toxicity or glutathione depletion due to the secondary alcohol, 1,3-dichloropropanol, irrespective of CYP2E1 induction. These results indicate that the primary alcohol isomer is metabolised to an aldehyde intermediate which depletes glutathione. Under basal conditions this metabolite appears to be effectively detoxified, but increased CYP2E1 activity and/or decreased aldehyde dehydrogenase activity promotes accumulation of metabolite, and therefore increases glutathione depletion and toxicity.
Hammond
A H
AH
School of Biomedical Sciences, Medical School, Queen's Medical Centre, Nottingham, UK.
Fry
J R
JR
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors; D000818:Animals; D002478:Cells, Cultured; D002728:Chlorohydrins / Q000633:toxicity*; D003484:Cyanamide / Q000633:toxicity*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism*; D007536:Isomerism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D020005:Propanols / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D000517:alpha-Chlorohydrin / Q000031:analogs & derivatives* / Q000633:toxicity
D002728:Chlorohydrins; D004791:Enzyme Inhibitors; D020005:Propanols; C033489:1,3-dichloro-2-propanol; C006463:allyl alcohol; D003484:Cyanamide; C076159:2,3-dichloro-1-propanol; D000517:alpha-Chlorohydrin; D000444:Aldehyde Dehydrogenase; D005978:Glutathione