Interaction of di-(2-ethylhexyl) phthalate with the pharmacological response and metabolic aspects of ethanol in mice

The interactions of di-(2-ethylhexyl) phthalate (DEHP) with the pharmacological response and metabolic aspects of ethanol in mice were investigated at oral doses of DEHP of 1.5, 3.0 and 7.5 g/kg or intraperitoneal doses of 3.7, 7.5 and 18.9 g/kg, administered once or daily for 7 days. A single oral or intraperitoneal administration of DEHP resulted in a significant increase in the ethanol-induced sleeping time, associated with an inhibition of alcohol dehydrogenase activity in liver; the effect of intraperitoneal administration was significant only at the highest dose. The activities of high and low Km aldehyde dehydrogenases in mouse liver were not affected by a single dose of DEHP by either route. Repeated oral doses of DEHP produced significant reductions in the ethanol-induced sleeping time and increases in the activities of alcohol and aldehyde dehydrogenases, whereas repeated intraperitoneal doses of DEHP significantly increased the sleeping time and decreased the activity of alcohol dehydrogenase, without any perceptible effect on the activities of aldehyde dehydrogenases. In vitro studies with mouse liver preparations revealed significant inhibition of alcohol dehydrogenase activity by mono-(2-ethylhexyl) phthalate and 2-ethylhexanol and of high and low Km aldehyde dehydrogenase activities by DEHP and mono-(2-ethylhexyl) phthalate at concentrations ranging from 0.03 to 1.00 mM. In all cases, in vitro enzyme inhibition by mono-(2-ethylhexyl) phthalate was most pronounced.