J Basic Clin Physiol Pharmacol 2018; aop Cagri Cakici, Turkan Yigitbasi*, Sule Ayla, Hadi Karimkhani, Feyza Bayramoglu, Pakize Yigit, Ertugrul Kilic and Nesrin Emekli Dose-dependent effects of vitamin 1,25(OH) 2 D 3 on oxidative stress and apoptosis https://doi.org/10.1515/jbcpp-2017-0121 Received August 4, 2017; accepted December 7, 2017 Abstract Background: The purpose of this study is to examine the dose-dependent effects of vitamin 1,25(OH) 2 D 3 on apopto- sis and oxidative stress. Methods: In this study, 50 male Balb/c mice were used as control and experiment groups. The mice were divided into 5 groups each consisting of 10 mice. Calcitriol was intraperitoneally administered as low dose, medium dose, medium-high dose and high dose vitamin D groups (at 0.5, 1, 5 and 10 μg/kg, respectively), for three times a week during 14 days. At the end of the study, annexin V was measured by enzyme-linked immunosorbent assay method, and total antioxidant capacity and total oxidant status values were measured by colorimetric method in serum. Hematoxylin eosin staining was performed in liver tissues and periodic acid schiff staining was performed in kidney tissues. Results: While comparing the results of medium-high dose (5 μg/kg) and high dose (10 μg/kg) vitamin D admin- istration to that of the control group, it was observed that serum antioxidant status and annexin V levels decreased and glomerular mesenchial matrix ratio increased in kidney (p < 0.05). In addition to these findings, in the group receiving high dose vitamin D (10 μg/kg), it was observed that the damage to the liver increased together with the the oxidative stress index values (p < 0.05). Conclusions: As a result, this study was the first in the lit- erature to report that use of high-dose vitamin D (10 μg/ kg) results in oxidant effect, rather than being an antioxi- dant, and causes severe histopathological toxicity in the liver and kidney. Keywords: apoptosis; calcitriol; oxidative stress; total oxidant status; total antioxidant capacity. Introduction Vitamin D is an important steroid hormone among fat-sol- uble vitamins [1, 2]. It plays a central role in the calcium and phosphorus hemostasis required for bone tissue cal- cification [3]. Vitamin D 2 is synthesized photochemically in plants, while vitamin D 3 is synthesized in dermis and epidermis by the effect of sunlight [4]. Vitamin D exists in the body in 25(OH)D and 1,25(OH) 2 D forms. 1,25(OH) 2 D 3 (calcitriol), which is the active form of vitamin D, binds to the vitamin D receptors (VDR) found in tissues and plays a role in the etiopathogenesis of dis- eases such as rickets and osteomalacia, which are related to the calcium metabolism, as well as autoimmune dis- eases, cardiovascular diseases, depression and cancer [5]. Besides, demonstration of VDR and 1-α hydroxylase (CYP27B1) enzyme in many tissues including pancreas, immunological system, macrophages, vascular endothe- lium, stomach, epidermis, colon, placenta, brain, and cancer cells implies that vitamin D might also have some unknown effects [6]. Apoptosis is an event of programmed cell death with different biochemical and genetic pathways that play a critical role in normal tissue development and homeosta- sis [7]. Calcitriol, which stimulates calcium entry, trans- fer, and calcium buffering in different cell types, plays a role in the regulation of the apoptosis process that deter- mines the outcome of health and disease in the cell [8, 9]. Increasing intracellular calcium triggers apoptosis by triggering apoptosis signaling pathways [10]. Besides, cal- citriol suppresses the expression of the anti-apoptotic pro- teins Bcl-2 and Bcl-xL and induces pro-apoptotic proteins Bax and Bak, likewise leading to cell apoptosis [11]. *Corresponding author: Turkan Yigitbasi, Biochemistry Department, Faculty of Medicine, Istanbul Medipol University, Ekinciler street No: 19 Kavacık, Beykoz/Istanbul, Turkey, E-mail: turkan.yigitbbasi@yahoo.com Cagri Cakici, Hadi Karimkhani, Feyza Bayramoglu and Nesrin Emekli: Biochemistry Department, Faculty of Medicine, Istanbul Medipol University, Beykoz, Istanbul, Turkey Sule Ayla: Histology and Embryology Department, Faculty of Medicine, Istanbul Medipol University, Beykoz, Istanbul, Turkey Pakize Yigit: Biostatistics and Medical Informatics Department, Faculty of Medicine, Istanbul Medipol University, Beykoz, Istanbul, Turkey Ertugrul Kilic: Physiology Department, Faculty of Medicine, Istanbul Medipol University, Beykoz, Istanbul, Turkey Brought to you by | Göteborg University - University of Gothenburg Authenticated Download Date | 2/12/18 4:22 PM