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

• Published in: Toxicology in vitro Vol. 54; pp. 237 - 242
• Main Authors: Hanioka, Nobumitsu, Isobe, Takashi, Ohkawara, Susumu, Ochi, Sadayuki, Tanaka-Kagawa, Toshiko, Jinno, Hideto
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-02-2019; Elsevier Science Ltd
• Subjects: Adolescent; Adult; Aged; Animals; Di(2-ethylhexyl) phthalate (DEHP); Diethylhexyl Phthalate - pharmacology; Dogs; Humans; Hydrolysis; Intestinal microsomes; Intestine; Intestines; Kinetics; Liver; Liver microsomes; Macaca fascicularis; Mammals; Metabolites; Mice; Microsomes; Microsomes - metabolism; Middle Aged; Monkeys; Mono(2-ethylhexyl) phthalate (MEHP); Plasticizers - pharmacology; Rats; Rats, Sprague-Dawley; Species; Species Specificity; Toxicity; Young Adult; Hydrolysis; MEHP; DEHP; Mono(2-ethylhexyl) phthalate (MEHP); Intestinal microsomes; Liver microsomes; Di(2-ethylhexyl) phthalate (DEHP)
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2018.10.006

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. Km or S50 values were similar among species, whereas Vmax exhibited species differences of approximately 9-fold. CLint or CLmax 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 Vmax and CLmax 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.
•DEHP hydrolysis in humans and experimental animals was examined in an in vitro system.•Hepatic hydrolysis activities were mice > dogs > monkeys ≥ rats > humans.•Intestinal hydrolysis activities were not detected in humans and dogs.•Intestinal hydrolysis activities were mice > rats > monkeys.