Ah. Hammond et Jr. Fry, Effect of cyanamide on toxicity and glutathione depletion in rat hepatocyte cultures: differences between two dichloropropanol isomers, CHEM-BIO IN, 122(2), 1999, pp. 107-115
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
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