Open AccessThe role of hepatic cytochrome P450s in the cytotoxicity of sertraline
Author(s) -
Si Chen,
Qiangen Wu,
Xilin Li,
Dongying Li,
Michelle Fan,
Zhen Ren,
Matthew Bryant,
Nan Mei,
Baitang Ning,
Lei Guo
Publication year - 2020
Publication title -
archives of toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.264
H-Index - 111
eISSN - 1432-0738
pISSN - 0340-5761
DOI - 10.1007/s00204-020-02753-y
Subject(s) - sertraline , cytotoxicity , topoisomerase , pharmacology , cytochrome p450 , cyp2d6 , fluoxetine , chemistry , biology , medicine , antidepressant , biochemistry , metabolism , in vitro , psychiatry , receptor , anxiety , serotonin
Sertraline, an antidepressant, is commonly used to manage mental health symptoms related to depression, anxiety disorders, and obsessive-compulsive disorder. The use of sertraline has been associated with rare but severe hepatotoxicity. Previous research demonstrated that mitochondrial dysfunction, apoptosis, and endoplasmic reticulum stress were involved in sertraline-associated cytotoxicity. In this study, we reported that after a 24-h treatment in HepG2 cells, sertraline caused cytotoxicity, suppressed topoisomerase I and IIα, and damaged DNA in a concentration-dependent manner. We also investigated the role of cytochrome P450 (CYP)-mediated metabolism in sertraline-induced toxicity using our previously established HepG2 cell lines individually expressing 14 CYPs (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7). We demonstrated that CYP2D6, 2C19, 2B6, and 2C9 metabolize sertraline, and sertraline-induced cytotoxicity was significantly decreased in the cells expressing these CYPs. Western blot analysis demonstrated that the induction of ɣH2A.X (a hallmark of DNA damage) and topoisomerase inhibition were partially reversed in CYP2D6-, 2C19-, 2B6-, and 2C9-overexpressing HepG2 cells. These data indicate that DNA damage and topoisomerase inhibition are involved in sertraline-induced cytotoxicity and that CYPs-mediated metabolism plays a role in decreasing the toxicity of sertraline.