Mechanism of Paroxetine-Induced Cell Death in Renal Tubular Cells

作者：Chen Wei Chuan; Huang Chorng Chih; Huang Chun Jen; Chien Jau Min; Lin Ko Long; Lu Yih Chau; Chen I Shu; Liu Shiuh Inn; Hsu Shu Shong; Chang Hong Tai; Chou Chiang Ting; Jan Chung Ren^*

来源：Basic and Clinical Pharmacology and Toxicology, 2008, 103(5): 407-413.

DOI：10.1111/j.1742-7843.2008.00319.x

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 mu M) 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 mu M 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.

• 出版日期2008-11