Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCB242

Poster Communications

Estrogen and Estrogen Receptor Agonists Protect Against Acetaminophen-induced Hepatorenal Toxicity in Rats

T. Koyuncuoğlu1, A. Yildirim1, G. Bastem2, B. Doğan2, E. Dönmez2, E. Temel2, E. Kuntsal Dertsiz3, M. Yüksel4, F. Ercan3, B. Yeğen1

1. Department of Physiology, Marmara University, School of Medicine, Istanbul, Turkey. 2. Medical Student at School of Medicine, Marmara University, Istanbul, Turkey. 3. Department of Histology and Embryology, Marmara University, School of Medicine, Istanbul, Turkey. 4. Vocational School of Health Services, Marmara University, Istanbul, Turkey.

Acetaminophen is the most widely used analgesic agent in the world. When taken at higher-than-recommended doses, acetaminophen has toxic effects on the liver and kidneys. Although clinical data reveal that women have a greater risk of experiencing drug-induced acute liver failure than men1, animal studies have reported that female mice showed a lower acetaminophen hepatotoxicity2. The aim of this study was to compare the impact of sex and ovarian hormones on acetaminophen-induced hepatorenal toxicity in rats and to elucidate the protective effects of estrogen and estrogen receptor agonists on the liver and kidneys. Experimental protocols were approved by the Marmara University Animal Ethics Committee. Under anesthesia (ketamine 100 mg/kg and xylazine 10 mg/kg, intraperitoneally) female Wistar Albino rats (n=49) had either ovariectomy (OVX) or sham-OVX. OVX groups received subcutaneously 17β-estradiol (1 mg/kg/day), ERβ-agonist diarylpropiolnitrile (1 mg/kg/day), ERα-agonist propyl pyrazole triol (1 mg/kg/day) or vehicle for 10 days starting at postsurgical 40th day. Male Wistar Albino rats (n=16) and sham-OVX groups were injected subcutaneously with vehicle for 10 days. At the end of the 7th week, rats received either acetaminophen (3 g/kg) or saline by orogastric gavage and 24 h later they were decapitated. Blood samples were obtained to measure serum alanine aminotransferase (ALT), aspartate transaminase (AST), blood urea nitrogen (BUN) and creatinine levels. Liver and kidney samples were obtained for histopathologic examination and for analyzing levels of tissue glutathione and myeloperoxidase activity. Data were analyzed using Mann Whitney-U and Student's t-tests. Histologically, renal and hepatic damage scores were elevated in all acetaminophen-treated female and male rats. Compared to their control groups, serum levels of AST, ALT, BUN, creatinine, renal myeloperoxidase activity were increased and hepatic glutathione level was decreased in vehicle plus acetaminophen-treated female and male rats (p<0.001), while hepatic myeloperoxidase activity was increased only in males (p<0.05). ERα-agonist reversed all parameters in liver and kidney. Pretreatment with ERβ-agonist or 17β-estradiol elevated hepatic glutathione levels and diminished creatinine and renal myeloperoxidase activity (p<0.05-0.01). Except for hepatic neutrophil infiltration, severity of acute acetaminophen-induced hepatorenal toxicity was not affected by sex difference or by the absence of ovarian hormones. On the other hand, pretreatment with estrogen or estrogen receptor agonists, via their antioxidant actions, provided protective effects on acetaminophen-induced hepatorenal toxicity.

Where applicable, experiments conform with Society ethical requirements