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Research ArticleArticle

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

Anam Hammid, John K. Fallon, Toni Lassila, Paula Vieiro, Anusha Balla, Francisco Gonzalez, Arto Urtti, Philip C. Smith, Ari Tolonen and Paavo Honkakoski
Drug Metabolism and Disposition December 2022, 50 (12) 1483-1492; DOI: https://doi.org/10.1124/dmd.122.000993
Anam Hammid
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.)
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John K. Fallon
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.)
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Toni Lassila
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.)
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Paula Vieiro
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.)
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Anusha Balla
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.)
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Francisco Gonzalez
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.)
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Arto Urtti
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.)
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Philip C. Smith
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.)
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Ari Tolonen
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.)
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Paavo Honkakoski
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.)
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Abstract

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.

Footnotes

    • Received June 15, 2022.
    • Accepted September 23, 2022.
  • This research work was carried out with the support of funding from the EU-ITN project OCUTHER (H2020-MSCA-ITN-2016, grant number 722717), the Doctoral Programme in Drug Research (University of Eastern Finland), and the Spanish Instituto de Salud Carlos III (grant number ISCIII – RD16/0008/0003, cofunded by FEDER).

  • No author has an actual or perceived conflict of interest with the contents of this article.

  • dx.doi.org/10.1124/dmd.122.000993.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 50 (12)
Drug Metabolism and Disposition
Vol. 50, Issue 12
1 Dec 2022
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Research ArticleArticle

Carboxylesterases in Human Eye Tissues

Anam Hammid, John K. Fallon, Toni Lassila, Paula Vieiro, Anusha Balla, Francisco Gonzalez, Arto Urtti, Philip C. Smith, Ari Tolonen and Paavo Honkakoski
Drug Metabolism and Disposition December 1, 2022, 50 (12) 1483-1492; DOI: https://doi.org/10.1124/dmd.122.000993

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Research ArticleArticle

Carboxylesterases in Human Eye Tissues

Anam Hammid, John K. Fallon, Toni Lassila, Paula Vieiro, Anusha Balla, Francisco Gonzalez, Arto Urtti, Philip C. Smith, Ari Tolonen and Paavo Honkakoski
Drug Metabolism and Disposition December 1, 2022, 50 (12) 1483-1492; DOI: https://doi.org/10.1124/dmd.122.000993
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