Contents lists available at ScienceDirect Life Sciences journal homepage: www.elsevier.com/locate/lifescie Estrogen receptor agonists protect against acetaminophen-induced hepatorenal toxicity in rats Türkan Koyuncuoğlu a , Alper Yıldırım a , Ekin K. Dertsiz b , Meral Yüksel c , Feriha Ercan b , Berrak Ç. Yeğen a, ⁎ a Department of Physiology, School of Medicine, Marmara University, Istanbul, Turkey b Department of Histology & Embryology, School of Medicine, Marmara University, Istanbul, Turkey c Department of Medical Laboratory, Vocational School of Health-Related Professions, Marmara University, Istanbul, Turkey ARTICLE INFO Keywords: Acetaminophen Estrogen receptor agonists Oxidative stress Hepatorenal toxicity ABSTRACT Aims: Acetaminophen-induced hepatorenal toxicity varies among sexes with controversial results among spe- cies. The aim was to compare the impact of sex and ovarian hormones on hepatorenal toxicity and to elucidate protective efects of estrogen and estrogen receptor (ER) agonists. Main methods: Under anesthesia, female rats underwent ovariectomy (OVX) or sham-OVX. Starting at post- surgical 40th day, OVX-rats received subcutaneously (each, 1 mg/kg/day) 17β-estradiol (E 2 ), ERβ-agonist (DPN) or ERα-agonist (PPT) for 10 days, while male and sham-OVX rats received vehicle for 10 days. Then, rats re- ceived either acetaminophen (3 g/kg) or saline by orogastric gavage and were decapitated at 24th h. Blood samples were obtained to measure serum ALT, AST, BUN, creatinine levels. Liver and kidney samples were obtained for histopathologic examination and for analyzing levels of luminol- and lucigenin-chemiluminescence, glutathione and myeloperoxidase activity. Key fndings: Compared to their control groups, levels of AST, ALT, BUN, creatinine, hepatic and renal myelo- peroxidase activity and chemiluminescence levels were increased, and hepatic glutathione level was decreased in acetaminophen-administered male groups, while ALT and hepatic chemiluminescence levels were not ele- vated in sham-OVX-rats. Both ER-agonists and E 2 reduced BUN, creatinine and reversed all oxidative parameters in renal tissues of OVX-rats. Additionally, ERα-agonist reversed all hepatic injury parameters, while ERβ-agonist elevated hepatic glutathione level. Signifcance: Acetaminophen toxicity in female rats presented with a more preserved hepatic function, while renal toxicity was not infuenced by sex or by the lack of ovarian hormones. Pretreatment with estrogen or ER agonists, via their antioxidant actions, provided protective efects on acetaminophen-induced hepatorenal toxicity. 1. Introduction Acetaminophen (N-acetyl-p-aminophenol; APAP) is an efective and commonly used analgesic and antipyretic drug with well-known anti- oxidant and anti-infammatory efects [1,2], but it exerts toxic efects when administered beyond its therapeutic doses. APAP-induced hepa- totoxicity is a leading cause of acute liver failure [3] with a 0.4% mortality in overdosed patients [4]. In therapeutic doses, APAP is ex- creted in the urine as glucuronide or sulfate metabolites (90%) or un- changed (2%), while the remaining is converted to N-acetyl-para-ben- zoquinoneimine (NAPQI) via the hepatic cytochrome 450 enzymes and excreted in the urine following its detoxifcation mostly by hepatic glutathione (GSH) [5,6]. However, overdose of APAP results in the saturation of sulfation and glucuronidation pathways, which causes overproduction of NAPQI and depletion of GSH stores, leading to oxi- dative injury and hepatocellular damage [7]. When compared to men, women present with diferent responses to treatments and more frequently sufer from the adverse efects of drugs [8] and are more sensitive to drug-induced hepatic damage [9–11], while the levels of cytochrome P450 3A4 (CYP3A4) were reported to be higher in women [12]. A large cohort study has reported that APAP- induced acute liver injury and liver failure were more common in women, and more female patients have required intensive care [13]. In parallel, female mice were shown to display a greater sensitivity to https://doi.org/10.1016/j.lfs.2020.118561 Received 13 August 2020; Received in revised form 16 September 2020; Accepted 1 October 2020 ⁎ Corresponding author at: Başıbüyük Mah, Maltepe Başıbüyük Yolu No. 9/1, 34854 Maltepe, Istanbul, Turkey. E-mail address: byegen@marmara.edu.tr (B.Ç. Yeğen). Life Sciences 263 (2020) 118561 Available online 10 October 2020 0024-3205/ © 2020 Published by Elsevier Inc. T