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Mechanism of Paroxetine‐Induced Cell Death in Renal Tubular Cells
Author(s) -
Chen WeiChuan,
Huang ChorngChih,
Huang ChunJen,
Chien JauMin,
Lin KoLong,
Lu YihChau,
Chen IShu,
Liu ShiuhInn,
Hsu ShuShong,
Chang HongTai,
Chou ChiangTing,
Jan ChungRen
Publication year - 2008
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2008.00319.x
Subject(s) - paroxetine , protein kinase c , kinase , protein kinase a , viability assay , apoptosis , pharmacology , chemistry , programmed cell death , biology , biochemistry , serotonin , receptor
Paroxetine belongs to the family of selective serotonin reuptake inhibitors. Much research has been performed on the in vitro effect of paroxetine; however, the effect of paroxetine on Madin‐Darby canine kidney renal tubular cells is unknown. The present study was aimed at exploring how paroxetine affects viability and to examine the underlying mechanisms. Paroxetine (15–200 µM) was shown to reduce cell viability via inducing apoptosis in a concentration‐dependent manner. Paroxetine‐induced cytotoxicity and apoptosis were not changed by the p38 mitogen‐activated protein kinase inhibitor SB203580 and the c‐Jun NH 2 ‐terminal kinase inhibitor SP600125, but was potentiated by the extracellular signal‐regulated kinase inhibitor PD98059; inhibited by GF 109203X, a protein kinase C inhibitor; and potentiated by phorbol 12‐myristate 13‐acetate, a protein kinase C activator. Paroxetine induced [Ca 2+ ] i rises; however, pre‐treatment with 1,2‐bis(o‐aminophenoxy)ethane‐N,N,N′,N′‐tetraacetic acid tetra(acetoxymethyl)ester, a Ca 2+ chelator, to prevent 20 µM paroxetine‐induced [Ca 2+ ] i rises did not protect cells from death. H‐89 (a protein kinase A inhibitor) and U73122 (a phospholipase C inhibitor) failed to alter paroxetine‐induced cell death. The results suggest that in Madin‐Darby canine kidney cells, paroxetine caused protein kinase C‐dependent, Ca 2+ ‐independent apoptosis which was potentiated by inhibition of the extracellular signal‐regulated kinase pathway.