Hydrolysis of di(2-ethylhexyl) phthalate in humans, monkeys, dogs, rats, and mice: An in vitro analysis using liver and intestinal microsomes

Abstract

Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer that is rapidly metabolized to mono(2-ethylhexyl) phthalate (MEHP), an active metabolite, in mammals. In the present study, the hydrolysis of DEHP by the liver and intestinal microsomes of humans, monkeys, dogs, rats, and mice was examined. The kinetics of liver microsomes fit the Michaelis-Menten model for humans, monkeys, and rats, and the Hill model for dogs and mice. K_m or S₅₀ values were similar among species, whereas V_max exhibited species differences of approximately 9-fold. CL_int or CL_max values were in the order of mice > dogs > monkeys ≥ rats > humans. Hydrolytic activity towards DEHP was not detected in the intestinal microsomes of humans or dogs. The kinetics of monkeys, rats, and mice followed the Hill model. In comparisons of the liver microsomes of each species, S₅₀ values were similar, while V_max and CL_max values (mice > rats > monkeys) were considerably lower (approximately 5-25%). These results suggest that hydrolytic activity towards DEHP in the liver and intestines markedly differ among humans and non-rodent and rodent experimental animals, and imply that species differences are closely associated with the toxicity of DEHP.

Keywords: Di(2-ethylhexyl) phthalate (DEHP); Hydrolysis; Intestinal microsomes; Liver microsomes; Mono(2-ethylhexyl) phthalate (MEHP).