Characterization of indoleamine-2,3-dioxygenase 1, tryptophan-2,3-dioxygenase, and Ido1/Tdo2 knockout mice.

Autor: Aslamkhan AG; Safety Assessment & Laboratory Animal Resources, Merck & Co, Inc., West Point, PA, USA; 770 Sumneytown Pike, WP45-313; West Point, PA 19486, USA. Electronic address: amy_aslamkhan@merck.com., Xu Q; Safety Assessment & Laboratory Animal Resources, Merck & Co, Inc., West Point, PA, USA., Loughlin A; Safety Assessment & Laboratory Animal Resources, Merck & Co, Inc., West Point, PA, USA., Vu H; Safety Assessment & Laboratory Animal Resources, Merck & Co, Inc., West Point, PA, USA., Pacchione S; Safety Assessment & Laboratory Animal Resources, Merck & Co, Inc., West Point, PA, USA., Bhatt B; Safety Assessment & Laboratory Animal Resources, Merck & Co, Inc., West Point, PA, USA., Garfinkel I; Safety Assessment & Laboratory Animal Resources, Merck & Co, Inc., West Point, PA, USA., Styring TG; Safety Assessment & Laboratory Animal Resources, Merck & Co, Inc., West Point, PA, USA., LaFranco-Scheuch L; Safety Assessment & Laboratory Animal Resources, Merck & Co, Inc., West Point, PA, USA., Pearson K; Safety Assessment & Laboratory Animal Resources, Merck & Co, Inc., West Point, PA, USA., Reynolds S; Safety Assessment & Laboratory Animal Resources, Merck & Co, Inc., West Point, PA, USA., Li N; Safety Assessment & Laboratory Animal Resources, Merck & Co, Inc., West Point, PA, USA., Zhou H; Genetics and Pharmacogenomics, Merck & Co, Inc., Kenilworth, NJ, USA., Miller JR; Quantitative Biosciences, Merck & Co, Inc., Boston, MA, USA., Solban N; Quantitative Biosciences, Merck & Co, Inc., Boston, MA, USA., Bass A; Safety Assessment & Laboratory Animal Resources, Merck & Co, Inc., West Point, PA, USA., Glaab WE; Safety Assessment & Laboratory Animal Resources, Merck & Co, Inc., West Point, PA, USA.
Jazyk: angličtina
Zdroj: Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2020 Nov 01; Vol. 406, pp. 115216. Date of Electronic Publication: 2020 Aug 29.
DOI: 10.1016/j.taap.2020.115216
Abstrakt: Indoleamine-2,3-dioxygenase 1 (IDO1) and tryptophan-2,3-dioxygenase 2 (TDO2) degrade tryptophan (Trp) to kynurenine (Kyn), and these enzymes have promise as therapeutic targets. A comprehensive characterization of potential safety liabilities of IDO1 and TDO2 inhibitors using knockout (KO) mice has not been assessed, nor has the dual Ido1/Tdo2 KO been reported. Here we characterized male and female mice with KOs for Ido1, Tdo2, and Ido1/Tdo2 and compared findings to the wild type (WT) mouse strain, evaluated for 14 days, using metabolomics, transcriptional profiling, behavioral analysis, spleen immunophenotyping, comprehensive histopathological analysis, and serum clinical chemistry. Multiple metabolomic changes were seen in KO mice. For catabolism of Trp to Kyn and anthranilic acid, both substrates were decreased in liver of Tdo2 and dual KO mice. Metabolism of Trp to serotonin and its metabolites resulted in an increase in 5-Hydroxyindole-3-acetic acid in the Tdo2 and dual KO mice. Ido1 and dual KO mice displayed a Kyn reduction in plasma but not in liver. Nicotinamide synthesis and conversion of glucose to lactic acid were not impacted. A slight decrease in serum alkaline phosphatase was seen in all KOs, and small changes in liver gene expression of genes unrelated to tryptophan metabolism were observed. Regarding other parameters, no genotype-specific changes were observed. In summary, this work shows metabolomic pathway changes for metabolites downstream of tryptophan in these KO mice, and suggests that inhibition of the IDO1 and TDO2 enzymes would be well tolerated whether inhibited individually or in combination since no safety liabilities were uncovered.
Competing Interests: Declaration of Competing Interest The authors declare that they have no competing financial interests or personal relationships that could influence the work reported in this paper.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: