Contents lists available at ScienceDirect Environmental Toxicology and Pharmacology journal homepage: www.elsevier.com/locate/etap In vivo investigation on the chronic hepatotoxicity induced by sertraline Mansour I. Almansour a , Yazun B. Jarrar b , Bashir M. Jarrar c, ⁎ a Zoology Department, College of Science, King Saud University, Saudi Arabia b Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Jordan c Department of Biological Sciences, College of Science, Jerash University, Jordan ARTICLE INFO Keywords: Sertraline Hepatotoxicity Gene expression Histological alterations Glycogen depletion Metabolizing enzymes ABSTRACT Although sertraline is widely prescribed as relatively safe antidepressant drug, hepatic toxicity was reported in some patients with sertraline treatment. The present study was conducted to investigate the morphometric, hepatotoxicity, and change in gene expression of drug metabolizing enzymes. Male healthy adult rabbits (Oryctolagus cuniculus) ranging from 1050 to 1100 g were exposed to oral daily doses of sertraline (0, 1, 2, 4, 8 mg/kg) for 9 weeks. The animals were subjected to morphometric, hepatohistological, histochemical and quantitative real-time polymerase chain reaction analyses. Sertraline chronic exposure induced morphometric changes and provoked histological and histochemical alterations including: hepatocytes hydropic degeneration, necrosis, nuclear alteration, sinusoidal dilation, bile duct hyperplasia, inflammatory cells infiltration, portal vessel congestion, Kupffer cells hyperplasia, portal fibrosis and glycogen depletion. In addition, the gene ex- pression of drug and arachidonic acid metabolizing enzymes were reduced significantly (p value < 0.05). The most affected genes were cyp4a12, ephx2, cyp2d9 and cyp1a2, demonstrating 5 folds or more down-regulation. These findings suggest that chronic sertraline treatment induced toxic histological alterations in the hepatic tissues and reduced the gene expression of drug metabolizing enzymes. Patients on chronic sertraline treatment may be on risk of hepatotoxicity with reduced capacity to metabolize drugs and fatty acids. 1. Introduction Sertraline, a selective serotonin reuptake inhibitor, is used in treatment of depression, obsessive–compulsive, panic, and social an- xiety disorders (Borkowska et al., 2002). In addition, this drug is used in alleviation symptoms of premenstrual dysphoric disorder, in treatment of premature ejaculation and vascular headache (Hoehn-Saric et al., 2000). Sertraline is the most prescribed antidepressant in US market (Grohol, 2014). Reports showed that the efficacy of sertraline for de- pression is similar to other classical tricyclic antidepressants, while its side effects are much less pronounced (Schramm et al., 2007). Studies showed that sertraline was capable of causing developmental toxicity and lowered feeding rates of the tadpoles of the African clawed frog (Xenopus laevis) at environmentally relevant concentrations via effects on the neuroendocrine system (Conners et al., 2009). Moreover, chronic exposure to sertraline caused prognosis breathlessness related to eosi- nophilic pneumonia and diffuse pulmonary fibrosis (Thornton et al., 2009). In addition, it was reported that sertraline administration in- duced ventricular tachycardia, bleeding and bilateral maculopathy (Patel et al., 2013; Eslami Shahrbabki and Eslami Shahrbabaki, 2014; Ewe et al., 2014). The hepatic side effects of sertraline were reported in multiple clinical studies (Collados et al., 2010; Park and Ishino, 2013; Suen et al., 2013). It was reported that sertraline exhibited severe hepatitis, cho- lestasis and bile duct paucity among psychiatric patients (Suen et al., 2013; Conrad et al., 2016). Also, it was reported that sertraline in- creased the gene expression of apoptosis and endoplasmic stress bio- markers in hepatic human hepG2 cell line and induced mitochondrial dysfunction in rat hepatic tissues (Chen et al., 2014a, b; Li et al., 2012). Some studies showed that sertraline induced the gene expression of stress biomarkers, such as PERK, IRE1α, and CHOP, in the endoplasmic reticulum of the human hepatic cell line HepG2 (Chen et al., 2014a). Furthermore, mRNA level of genes involved in endogenous and xeno- biotic compounds metabolism was widely changed after larval zebra fish were exposed to sertraline (Park et al., 2012). Limited studies were carried out on the influence of sertraline in the liver, with lack of studies conducted on the histomorpholometric influ- ence of this drug and on the mRNA levels of drug metabolizing enzymes in the liver. With these objectives, the present study aimed to investigate the hepatic histomorphological changes and gene expression of phase I, II and arachidonic-cytochrome P450 (CYP450) enzymes in the hepatic tissues of healthy male rabbits after chronic sertraline exposure. https://doi.org/10.1016/j.etap.2018.05.021 Received 13 March 2018; Received in revised form 25 May 2018; Accepted 30 May 2018 ⁎ Corresponding author at: Department of Biological Sciences, College of Science, Jerash University, Jerash 26150, P.O. Box: 311, Jordan. E-mail address: mmansour@ksu.edu.sa (B.M. Jarrar). Environmental Toxicology and Pharmacology 61 (2018) 107–115 Available online 30 May 2018 1382-6689/ © 2018 Elsevier B.V. All rights reserved. T