Fodipir and its dephosphorylated derivative dipyridoxyl ethyldiamine are involved in mangafodipir-mediated cytoprotection against 7β-hydroxycholesterol-induced cell death.
OBJECTIVE
Mangafodipir exerts pharmacological effects, including vascular relaxation and protection against oxidative stress and cell death induced by oxysterols. Additionally, mangafodipir has been proposed for cardiovascular imaging. The primary metabolites of mangafodipir, manganese dipyridoxyl ethyldiamine (MnPLED) and its constituent dipyridoxyl diphosphate (Dp-dp) also known as fodipir, are pharmacologically active. However, whether they affect oxysterol-induced cytotoxicity is currently unknown. In this study, we examine whether the mangafodipir metabolite affects 7β-hydroxycholesterol (7β-OH)-induced cell death and identify the underlying mechanisms.


METHODS
U937 cells were pretreated or not with mangafodipir substrate (Ms; 200 µm), MnPLED (100 µmol/l) or Dp-dp (100 µmol/l) for 8 h and then exposed to 7β-OH (28 µmol/l) for 18 h.


RESULTS
Our results revealed that pretreatment with MnPLED or Dp-dp protected against 7β-OH-induced cellular reactive oxygen species (ROS) production, apoptosis, and lysosomal membrane permeabilization (LMP). MnPLED and Dp-dp, in par with Ms, confer protection against 7β-OH-induced cytotoxicity by reducing cellular ROS and stabilization of the lysosomal membrane.


CONCLUSIONS
These results suggest that fodipir is the pharmacologically active part in the structure of mangafodipir, which prevents 7β-OH-induced cell death by attenuating cellular ROS and by preventing LMP. In addition, MnPLED, which is the dephosphorylated product of fodipir, exerts a similar protective effect against 7β-OH-induced cytotoxicity. This result indicates that dephosphorylation of fodipir does not affect its pharmacological actions. Altogether our result confirms the cytoprotective effect of mangafodipir and justifies its potential use as a cytoprotective adjuvant.
Division of Experimental Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
Amit
A
Laskar
Rolf G G
RG
Andersson
Wei
W
Li
D016923:Cell Death / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects*; D004492:Edetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D006888:Hydroxycholesterols; D008247:Lysosomes / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology*; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D020298:U937 Cells
D006888:Hydroxycholesterols; D020011:Protective Agents; D017382:Reactive Oxygen Species; C011724:cholest-5-en-3 beta,7 alpha-diol; D011732:Pyridoxal Phosphate; D004492:Edetic Acid; C060076:N,N'-bis(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid