Inhibitory effects of organophosphate esters on carboxylesterase activity of rat liver microsomes

• Published in: Chemico-biological interactions Vol. 327; p. 109148
• Main Authors: Tsugoshi, Yukie, Watanabe, Yoko, Tanikawa, Yuka, Inoue, Chika, Sugihara, Kazumi, Kojima, Hiroyuki, Kitamura, Shigeyuki
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 25.08.2020
• Subjects: Carboxylesterase; Inhibition; Organophosphate esters; Rat liver microsomes; Organophosphate esters; Inhibition; Carboxylesterase; Rat liver microsomes
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2020.109148

We investigated the inhibitory effects of 13 organophosphate esters (OPEs) and hydrolytic metabolites on the carboxylesterase activity of rat liver microsomes in vitro in order to examine whether there might be a potential impact on human health, and to elucidate the structure activity relationship. Among the test compounds, 2-ethylhexyl diphenyl phosphate (EDPhP) was the most potent inhibitor of carboxylesterase activity, as measured in terms of 4-nitrophenol acetate hydrolase activity, followed by tri-m-cresyl phosphate (TmCP), cresyl diphenyl phosphate (CDPhP) and triphenyl phosphate (TPhP). The IC50 values were as follows: EDPhP (IC50: 0.03 μM) > TmCP (0.4 μM) > CDPhP (0.8 μM) > TPhP (14 μM) > tris(1,3-dichloro-2-propyl) phosphate (17 μM) > tris(2-ethylhexyl) phosphate (77 μM) > tri-n-propyl phosphate (84 μM) > tris(2-chloroethyl) phosphate (104 μM) > tris(2-butoxyethyl) phosphate (124 μM) > tri-n-butyl phosphate (230 μM). The IC50 value of EDPhP was three orders of magnitude lower than that of bis(4-nitrophenyl) phosphate, which is widely used as an inhibitor of carboxylesterase. Trimethyl phosphate, triethyl phosphate and tris(2-chloroisopropyl) phosphate slightly inhibited the carboxylesterase activity; their IC50 values were above 300 μM. Lineweaver-Burk plots indicated that the inhibition by several OPEs was non-competitive. Diphenyl and monophenyl phosphates, which are metabolites of TPhP, showed weaker inhibitory effects than that of TPhP. •We examined carboxylesterase inhibition by organophosphate esters (OPEs).•2-Ethylhexyl diphenyl phosphate was the most potent inhibitor among tested OPEs.•Aryl OPEs were strong rat liver microsomal carboxylesterase inhibitors.•Di- or mono-substituted derivatives of OPEs showed markedly decreased inhibition.•OPEs bearing a bulky substituent showed greater carboxylesterase-inhibitory effects.