title: Contribution of membrane trafficking perturbation to retinal toxicity.
abstract: The retina is a highly structured tissue that is formed by layers containing 7 different cell types. The photoreceptor cell is a specialized type of neuron in the retina that is capable of absorbing and converting light into electrophysiological signals. There is a constant renewal process for photoreceptors consisting of intermittent shedding of the distal tips of the photosensitive outer segment and subsequent phagocytosis (uptake, degradation and recycling) by retinal pigmented epithelial (RPE) cells. This rebuilding process is essential for vision and the survival of photoreceptors and RPE cells. Drugs with a basic moiety have the potential to accumulate in the lysosome and impair its functions including the phagocytosis process, which could hinder clearance of outer segments and ultimately induce retinopathy. To determine the prevalence of this cellular mechanism in retinal toxicity, a collection of proprietary compounds associated with retinal toxicity were subjected to a battery of in vitro tests using the human adult retinal pigmented epithelium cell line, ARPE-19. The tests included a phagocytosis assay, and lysosomal and autophagosomal staining. The compounds that induced retinopathy clustered in the basic and lipophilic region, which drives lysosomal sequestration. This accumulation coincided with phagocytosis inhibition and an increase in autophagosome staining, suggesting a blockage of the membrane trafficking process. A correlation between the physicochemical properties and in vitro lysosomal pathway effects was established. These data reveal the importance of physicochemical properties of compounds and lysosome accumulation as a potential mechanism for drug-induced retinopathy and demonstrate the usefulness of in vitro screening in predicting this liability.
authors.affiliation: *Drug Safety Research and Development, Pfizer Inc., San Diego, California, Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut, and Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., San Diego, California.
authors.forename: Su
authors.initials: S
authors.lastname: Khoh-Reiter
authors.affiliation: *Drug Safety Research and Development, Pfizer Inc., San Diego, California, Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut, and Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., San Diego, California.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Sokolowski
authors.affiliation: *Drug Safety Research and Development, Pfizer Inc., San Diego, California, Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut, and Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., San Diego, California.
authors.forename: Bart
authors.initials: B
authors.lastname: Jessen
authors.affiliation: *Drug Safety Research and Development, Pfizer Inc., San Diego, California, Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut, and Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., San Diego, California.
authors.forename: Mark
authors.initials: M
authors.lastname: Evans
authors.affiliation: *Drug Safety Research and Development, Pfizer Inc., San Diego, California, Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut, and Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., San Diego, California.
authors.forename: Deepak
authors.initials: D
authors.lastname: Dalvie
authors.affiliation: *Drug Safety Research and Development, Pfizer Inc., San Diego, California, Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut, and Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., San Diego, California shuyan.lu@pfizer.com.
authors.forename: Shuyan
authors.initials: S
authors.lastname: Lu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010587:Phagocytosis / Q000187:drug effects; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D021381:Protein Transport; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein
keywords: lysosomotropic; phagocytosis; retinal toxicity