title: [(3) H]-L685,458 binding sites are abundant in multiple peripheral organs in rats: implications for safety assessment of putative γ-secretase targeting drugs.
abstract: γ-Secretase is a multimeric enzyme complex that carries out proteolytic processing to a variety of cellular proteins. It is currently explored as a therapeutic target for Alzheimer's disease (AD) and cancer. Mechanism-based toxicity needs to be thoroughly evaluated for γ-secretase inhibitory and/or modulatory drugs. This study comparatively assessed putative γ-secretase catalytic sites in rat peripheral tissues relative to brain and explored an effort of its pharmacological inhibition on hair regeneration. Using [(3) H]-labelled L685,458, a potent γ-secretase inhibitor, as probe, we found more abundant presence of γ-secretase binding sites in the liver, gastrointestinal tract, hair follicle, pituitary gland, ovary and testis, as compared to the brain. Local application of L658,458 delayed vibrissal regrowth following whisker removal. These results suggest that γ-secretase may execute important biological functions in many peripheral systems, as in the brain. The development of γ-secretase inhibitors/modulators for AD and cancer therapy should include close monitoring of toxicological panels for hepatic, gastrointestinal, endocrinal and reproductive functions.
authors.affiliation: Department of Anatomy and Neurobiology, Central South University School of Basic Medical Science, Changsha, China; Department of Pharmacy, Changsha Health Vocational College, Changsha, China.
authors.forename: Zhi-Ying
authors.initials: ZY
authors.lastname: Yang
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Li
authors.forename: Ling
authors.initials: L
authors.lastname: Xiao
authors.forename: Lin
authors.initials: L
authors.lastname: Mou
authors.forename: Yan
authors.initials: Y
authors.lastname: Cai
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.forename: Xue-Gang
authors.initials: XG
authors.lastname: Luo
authors.forename: Xiao-Xin
authors.initials: XX
authors.lastname: Yan
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000187:drug effects; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects; D002219:Carbamates / Q000009:adverse effects / Q000378:metabolism*; D004151:Dipeptides / Q000009:adverse effects / Q000378:metabolism*; D005260:Female; D006197:Hair / Q000187:drug effects / Q000254:growth & development; D006321:Heart / Q000187:drug effects; D007583:Jejunum / Q000187:drug effects; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008297:Male; D010902:Pituitary Gland / Q000187:drug effects; D051381:Rats; D012867:Skin / Q000187:drug effects; D013737:Testis / Q000187:drug effects; D014018:Tissue Distribution
chemical_list: D002219:Carbamates; D004151:Dipeptides; C410009:L 685458; D053829:Amyloid Precursor Protein Secretases