Effect of ATP-Binding Cassette Transporters on Antipsychotics-Induced Cytotoxicity in Blood Brain Barrier Endothelial Cells
El-Zalabany, L., Mosad, S., Awad, M., Smith, P., Elmorsy, E. (2014). Effect of ATP-Binding Cassette Transporters on Antipsychotics-Induced Cytotoxicity in Blood Brain Barrier Endothelial Cells. EKB Journal Management System, 22(2), 89-105. doi: 10.21608/mjfmct.2014.47661
Laila El-Zalabany; Soad M. Mosad; Mahmoud E. Awad; Paul A. Smith; Ekramy M. Elmorsy. "Effect of ATP-Binding Cassette Transporters on Antipsychotics-Induced Cytotoxicity in Blood Brain Barrier Endothelial Cells". EKB Journal Management System, 22, 2, 2014, 89-105. doi: 10.21608/mjfmct.2014.47661
El-Zalabany, L., Mosad, S., Awad, M., Smith, P., Elmorsy, E. (2014). 'Effect of ATP-Binding Cassette Transporters on Antipsychotics-Induced Cytotoxicity in Blood Brain Barrier Endothelial Cells', EKB Journal Management System, 22(2), pp. 89-105. doi: 10.21608/mjfmct.2014.47661
El-Zalabany, L., Mosad, S., Awad, M., Smith, P., Elmorsy, E. Effect of ATP-Binding Cassette Transporters on Antipsychotics-Induced Cytotoxicity in Blood Brain Barrier Endothelial Cells. EKB Journal Management System, 2014; 22(2): 89-105. doi: 10.21608/mjfmct.2014.47661

Effect of ATP-Binding Cassette Transporters on Antipsychotics-Induced Cytotoxicity in Blood Brain Barrier Endothelial Cells

Mansoura Journal of Forensic Medicine and Clinical Toxicology
Article 6, Volume 22, Issue 2, July 2014, Page 89-105  XML PDF (32.14 MB)
Document Type: Original Article
DOI: 10.21608/mjfmct.2014.47661
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Authors
Laila El-Zalabany1; Soad M. Mosad2; Mahmoud E. Awad2; Paul A. Smith3; Ekramy M. Elmorsy2
1Forensic Med. & Clin. Toxicology, Mansoura Faculty of Medicine
2Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Mansoura University, Egypt
3Cellular signalling department, Biomedical Sciences School, University of Nottingham, UK
Abstract
The ATP-binding cassette (ABC) transporters as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) have been identified in several physiological sites. It has been suggested to play an important role in disposition of many drugs and environmental toxins. This study investigated the effects of antipsychotics (APs), including chlorpromazine (CPZ), risperidone (RIS), clozapine (CLZ), haloperidol (HAL), in their cytotoxic concentrations, on functions of P-gp and BCRP in human micro-vascular endothelial cells (HMVECs) of blood brain barrier (BBB). Firstly, the cytotoxic effects of APs were studied using alamar blue (AB) assay and inhibitory concentrations 50 (ICs50) were estimated. Presence of both P-gp and BCRP transporters was confirmed biochemically and functionally by western blotting and rhodamine-123 (Rh123) assays respectively. Verapamil and Ko134 were used as inhibitors for P-gp and BCRP transporters respectively. Lastly, the effect of transporters inhibitors verapamil (100 ∝ M) and Ko134 (10nM) on APs –induced cytotoxicity was studied. Results showed that APs were cytotoxic to the HMVECs of BBB. CPZ was the most cytotoxic. Presence of P-gp and BCRP was confirmed biochemically and functionally. In ICs50, APs showed inhibitory effect on the transporters, using Rh123 as a substrate. Also, transporters blockade increased APs-induced cytotoxicity with variable degrees. The present results suggest that a potential source of pharmacokinetic interactions exist between ABC transporters substrates and several antipsychotics in toxic conditions. 
Keywords
Antipsychotics; Cytotoxicity; P-glycoprotein transporter; Breast cancer resistance protein; Blood brain barrier
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