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 w as investigated in 24 h rat hepatocyte cultures. Cyanamide pre-treatment ha d no effect on nitrophenol hydroxylase, 7-methoxy-, 7-ethoxy- or 7-benzylox yresorufin O-dealkylase activities in 24 h cultures from untreated rats, an d had no effect on intracellular glutathione content in cultures from untre ated rats, or in cultures from isoniazid-treated rats in which cytochrome P 4502E1 (CYP2E1) is increased. In cultures from untreated animals the primar y alcohol, 2,3-dichloropropanol, was not toxic and did not significantly de plete glutathione. Cyanamide pre-treatment however, potentiated both toxici ty and glutathione depletion. Induction of CYP2E1 also potentiated the toxi city 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 a lcohol, 1,3-dichloropropanol, irrespective of CYP2E1 induction. These resul ts indicate that the primary alcohol isomer is metabolised to an aldehyde i ntermediate which depletes glutathione. Under basal conditions this metabol ite appears to be effectively detoxified, but increased CYP2E1 activity and /or decreased aldehyde dehydrogenase activity promotes accumulation of meta bolite, and therefore increases glutathione depletion and toxicity. (C) 199 9 Elsevier Science Ireland Ltd. All rights reserved.