Isobe_2023_Chem.Biol.Interact_372_110353

Phthalates are widely used plasticizers that are primarily and rapidly metabolized to monoester phthalates in mammals. In the present study, the hydrolysis of dibutyl phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP) in the human liver, small intestine, kidney, and lung was examined by the catalytic, kinetic, and inhibition analyses using organ microsomal and cytosolic fractions and recombinant carboxylesterases (CESs). The V(max) (y-intercept) values based on the Eadie-Hofstee plots of DBP hydrolysis were livers>ssmall intestines>skidneys>slung in microsomes, and livers>ssmall intestines>slungs>skidney in cytosol, respectively. The CL(int) values (x-intercept) were small intestines>slivers>skidneys>slung in both microsomes and cytosol. The V(max) and CL(int) or CL(max) values of DEHP hydrolysis were small intestines>slivers>skidneys>slung in both microsomes and cytosol. Bis(4-nitrophenyl) phosphate (BNPP) effectively inhibited the activities of DBP and DEHP hydrolysis in the microsomes and cytosol of liver, small intestine, kidney, and lung. Although physostigmine also potently inhibited DBP and DEHP hydrolysis activities in both the microsomes and cytosol of the small intestine and kidney, the inhibitory effects in the liver and lung were weak. In recombinant CESs, the V(max) values of DBP hydrolysis were CES1 (CES1b, CES1c)s>sCES2, whereas the CL(max) values were CES2s>sCES1 (CES1b, CES1c). On the other hand, the V(max) and CL(max) values of DEHP hydrolysis were CES2s>sCES1 (CES1b, CES1c). These results suggest an extensive organ-dependence of DBP and DEHP hydrolysis due to CES expression, and that CESs are responsible for the metabolic activation of phthalates.