Activity and Expression of Carboxylesterases and Arylacetamide Deacetylase in Human Ocular Tissues.

Autor:	Hammid A; School of Pharmacy, University of Eastern Finland, Kuopio, Finland (A.H., A.B., A.U., P.H.); Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); Admescope Ltd, Oulu, Finland (T.L., A.T.); Biobank at the University Hospital at Santiago de Compostela, Santiago de Compostela, Spain (P.V.); Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela, Santiago de Compostela, Spain (F.G.); Service of Ophthalmology, University Hospital of Santiago de Compostela and Fundacion Instituto de Investigacion Sanitaria de Santiago de Compostela, Santiago de Compostela (F.G.); and Faculty of Pharmacy, University of Helsinki, Helsinki, Finland (A.U.) paavo.honkakoski@uef.fi anam.hammid@uef.fi., Fallon JK; School of Pharmacy, University of Eastern Finland, Kuopio, Finland (A.H., A.B., A.U., P.H.); Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); Admescope Ltd, Oulu, Finland (T.L., A.T.); Biobank at the University Hospital at Santiago de Compostela, Santiago de Compostela, Spain (P.V.); Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela, Santiago de Compostela, Spain (F.G.); Service of Ophthalmology, University Hospital of Santiago de Compostela and Fundacion Instituto de Investigacion Sanitaria de Santiago de Compostela, Santiago de Compostela (F.G.); and Faculty of Pharmacy, University of Helsinki, Helsinki, Finland (A.U.)., Lassila T; School of Pharmacy, University of Eastern Finland, Kuopio, Finland (A.H., A.B., A.U., P.H.); Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); Admescope Ltd, Oulu, Finland (T.L., A.T.); Biobank at the University Hospital at Santiago de Compostela, Santiago de Compostela, Spain (P.V.); Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela, Santiago de Compostela, Spain (F.G.); Service of Ophthalmology, University Hospital of Santiago de Compostela and Fundacion Instituto de Investigacion Sanitaria de Santiago de Compostela, Santiago de Compostela (F.G.); and Faculty of Pharmacy, University of Helsinki, Helsinki, Finland (A.U.)., Vieiro P; School of Pharmacy, University of Eastern Finland, Kuopio, Finland (A.H., A.B., A.U., P.H.); Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); Admescope Ltd, Oulu, Finland (T.L., A.T.); Biobank at the University Hospital at Santiago de Compostela, Santiago de Compostela, Spain (P.V.); Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela, Santiago de Compostela, Spain (F.G.); Service of Ophthalmology, University Hospital of Santiago de Compostela and Fundacion Instituto de Investigacion Sanitaria de Santiago de Compostela, Santiago de Compostela (F.G.); and Faculty of Pharmacy, University of Helsinki, Helsinki, Finland (A.U.)., Balla A; School of Pharmacy, University of Eastern Finland, Kuopio, Finland (A.H., A.B., A.U., P.H.); Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); Admescope Ltd, Oulu, Finland (T.L., A.T.); Biobank at the University Hospital at Santiago de Compostela, Santiago de Compostela, Spain (P.V.); Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela, Santiago de Compostela, Spain (F.G.); Service of Ophthalmology, University Hospital of Santiago de Compostela and Fundacion Instituto de Investigacion Sanitaria de Santiago de Compostela, Santiago de Compostela (F.G.); and Faculty of Pharmacy, University of Helsinki, Helsinki, Finland (A.U.)., Gonzalez F; School of Pharmacy, University of Eastern Finland, Kuopio, Finland (A.H., A.B., A.U., P.H.); Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); Admescope Ltd, Oulu, Finland (T.L., A.T.); Biobank at the University Hospital at Santiago de Compostela, Santiago de Compostela, Spain (P.V.); Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela, Santiago de Compostela, Spain (F.G.); Service of Ophthalmology, University Hospital of Santiago de Compostela and Fundacion Instituto de Investigacion Sanitaria de Santiago de Compostela, Santiago de Compostela (F.G.); and Faculty of Pharmacy, University of Helsinki, Helsinki, Finland (A.U.)., Urtti A; School of Pharmacy, University of Eastern Finland, Kuopio, Finland (A.H., A.B., A.U., P.H.); Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); Admescope Ltd, Oulu, Finland (T.L., A.T.); Biobank at the University Hospital at Santiago de Compostela, Santiago de Compostela, Spain (P.V.); Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela, Santiago de Compostela, Spain (F.G.); Service of Ophthalmology, University Hospital of Santiago de Compostela and Fundacion Instituto de Investigacion Sanitaria de Santiago de Compostela, Santiago de Compostela (F.G.); and Faculty of Pharmacy, University of Helsinki, Helsinki, Finland (A.U.)., Smith PC; School of Pharmacy, University of Eastern Finland, Kuopio, Finland (A.H., A.B., A.U., P.H.); Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); Admescope Ltd, Oulu, Finland (T.L., A.T.); Biobank at the University Hospital at Santiago de Compostela, Santiago de Compostela, Spain (P.V.); Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela, Santiago de Compostela, Spain (F.G.); Service of Ophthalmology, University Hospital of Santiago de Compostela and Fundacion Instituto de Investigacion Sanitaria de Santiago de Compostela, Santiago de Compostela (F.G.); and Faculty of Pharmacy, University of Helsinki, Helsinki, Finland (A.U.)., Tolonen A; School of Pharmacy, University of Eastern Finland, Kuopio, Finland (A.H., A.B., A.U., P.H.); Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); Admescope Ltd, Oulu, Finland (T.L., A.T.); Biobank at the University Hospital at Santiago de Compostela, Santiago de Compostela, Spain (P.V.); Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela, Santiago de Compostela, Spain (F.G.); Service of Ophthalmology, University Hospital of Santiago de Compostela and Fundacion Instituto de Investigacion Sanitaria de Santiago de Compostela, Santiago de Compostela (F.G.); and Faculty of Pharmacy, University of Helsinki, Helsinki, Finland (A.U.)., Honkakoski P; School of Pharmacy, University of Eastern Finland, Kuopio, Finland (A.H., A.B., A.U., P.H.); Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); Admescope Ltd, Oulu, Finland (T.L., A.T.); Biobank at the University Hospital at Santiago de Compostela, Santiago de Compostela, Spain (P.V.); Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela, Santiago de Compostela, Spain (F.G.); Service of Ophthalmology, University Hospital of Santiago de Compostela and Fundacion Instituto de Investigacion Sanitaria de Santiago de Compostela, Santiago de Compostela (F.G.); and Faculty of Pharmacy, University of Helsinki, Helsinki, Finland (A.U.) paavo.honkakoski@uef.fi anam.hammid@uef.fi.
Jazyk:	angličtina
Zdroj:	Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2022 Dec; Vol. 50 (12), pp. 1483-1492. Date of Electronic Publication: 2022 Oct 04.
DOI:	10.1124/dmd.122.000993
Abstrakt:	As a multitissue organ, the eye possesses unique anatomy and physiology, including differential expression of drug-metabolizing enzymes. Several hydrolytic enzymes that play a major role in drug metabolism and bioactivation of prodrugs have been detected in ocular tissues, but data on their quantitative expression is scarce. Also, many ophthalmic drugs are prone to hydrolysis. Metabolic characterization of individual ocular tissues is useful for the drug development process, and therefore, seven individual ocular tissues from human eyes were analyzed for the activity and expression of carboxylesterases (CESs) and arylacetamide deacetylase (AADAC). Generic and selective human esterase substrates 4-nitrophenyl acetate (most esterases), D-luciferin methyl ester (CES1), fluorescein diacetate and procaine (CES2), and phenacetin (AADAC) were applied to determine the enzymes' specific activities. Enzyme kinetics and inhibition studies were performed with isoform-selective inhibitors digitonin (CES1) and verapamil and diltiazem (CES2). Enzyme contents were determined using quantitative targeted proteomics, and CES2 expression was confirmed by western blotting. The expression and activity of human CES1 among ocular tissues varied by >10-fold, with the highest levels found in the retina and iris-ciliary body. In contrast, human CES2 expression appeared lower and more similar between tissues, whereas AADAC could not be detected. Inhibition studies showed that hydrolysis of fluorescein diacetate is also catalyzed by enzymes other than CES2. This study provides, for the first time, quantitative information on the tissue-dependent expression of human ocular esterases, which can be useful for the development of ocular drugs, prodrugs, and in pharmacokinetic modeling of the eye. SIGNIFICANCE STATEMENT: Novel and comprehensive data on the protein expression and activities of carboxylesterases from individual human eye tissues are generated. In combination with previous reports on preclinical species, this study will improve the understanding of interspecies differences in ocular drug metabolism and aid the development of ocular pharmacokinetics models. (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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