Retinal toxicity, in vivo and in vitro, associated with inhibition of nicotinamide phosphoribosyltransferase

• Published in: Toxicological sciences 2015-03, Vol.144 (1), p.163-172
• Main Authors: Zabka, Tanja S, Singh, Jatinder, Dhawan, Preeti, Liederer, Bianca M, Oeh, Jason, Kauss, Mara A, Xiao, Yang, Zak, Mark, Lin, Tori, McCray, Bobbi, La, Nghi, Nguyen, Trung, Beyer, Joseph, Farman, Cynthia, Uppal, Hirdesh, Dragovich, Peter S, O'Brien, Thomas, Sampath, Deepak, Misner, Dinah L
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Cell Survival - drug effects; Cyanides - toxicity; Cytokines - antagonists & inhibitors; Cytokines - genetics; Cytokines - metabolism; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - toxicity; Female; Gene Expression Regulation, Enzymologic; Guanidines - toxicity; Heterocyclic Compounds, 2-Ring - toxicity; Humans; Male; Mice, Nude; Molecular Structure; Niacin - pharmacology; Nicotinamide Phosphoribosyltransferase - antagonists & inhibitors; Nicotinamide Phosphoribosyltransferase - genetics; Nicotinamide Phosphoribosyltransferase - metabolism; Nicotinamide-Nucleotide Adenylyltransferase - metabolism; Pentosyltransferases - metabolism; Rats, Sprague-Dawley; Retinal Pigment Epithelium - drug effects; Retinal Pigment Epithelium - enzymology; Retinal Pigment Epithelium - pathology; Risk Assessment; RNA, Messenger - metabolism; Species Specificity; Structure-Activity Relationship; Sulfones - toxicity
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfu268

Nicotinamide phosphoribosyltransferase (NAMPT) is a pleiotropic protein with intra- and extra-cellular functions as an enzyme, cytokine, growth factor, and hormone. NAMPT is of interest for oncology, because it catalyzes the rate-limiting step in the salvage pathway to generate nicotinamide adenine dinucleotide (NAD), which is considered a universal energy- and signal-carrying molecule involved in cellular energy metabolism and many homeostatic functions. This manuscript describes NAMPT inhibitor-induced retinal toxicity that was identified in rodent safety studies. This toxicity had a rapid onset and progression and initially targeted the photoreceptor and outer nuclear layers. Using in vivo safety and efficacy rodent studies, human and mouse cell line potency data, human and rat retinal pigmented epithelial cell in vitro systems, and rat mRNA expression data of NAMPT, nicotinic acid phosphoribosyltransferase, and nicotinamide mononucleotide adenylyltransferease (NMNAT) in several tissues from rat including retina, we demonstrate that the retinal toxicity is on-target and likely human relevant. We demonstrate that this toxicity is not mitigated by coadministration of nicotinic acid (NA), which can enable NAD production through the NAMPT-independent pathway. Further, modifying the physiochemical properties of NAMPT inhibitors could not sufficiently reduce retinal exposure. Our work highlights opportunities to leverage appropriately designed efficacy studies to identify known and measurable safety findings to screen compounds more rapidly and reduce animal use. It also demonstrates that in vitro systems with the appropriate cell composition and relevant biology and toxicity endpoints can provide tools to investigate mechanism of toxicity and the human translation of nonclinical safety concerns.