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Atorvastatin Acts Synergistically with N-acetyl Cysteine to Provide Therapeutic Advantage against Fas-Activated Erythrocyte Apoptosis during Chronic Arsenic Exposure in Rats.

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Title Atorvastatin Acts Synergistically with N-acetyl Cysteine to Provide Therapeutic Advantage against Fas-Activated Erythrocyte Apoptosis during Chronic Arsenic Exposure in Rats.
 
Creator Biswas, Debabrata
Sen, Gargi
Sarkar, Avik
Biswas, Tuli
 
Subject Cell Biology & Physiology
 
Description Arsenic is an environmental toxicant that reduces the lifespan of circulating erythrocytes during chronic
exposure. Our previous studies had indicated involvement of hypercholesterolemia and reactive oxygen
species (ROS) in arsenic-induced apoptotic death of erythrocytes. In this study, we have shown an effective
recovery from arsenic-induced death signaling in erythrocytes in response to treatment with atorvastatin
(ATV) and N-acetyl cysteine (NAC) in rats. Our results emphasized on the importance of cholesterol in the
promotion of ROS-mediated Fas signaling in red cells. Arsenic-induced activation of caspase 3 was associated
with phosphatidylserine exposure on the cell surface and microvesiculation of erythrocyte membrane.
Administration of NAC in combination with ATV, proved to be more effective than either of the drugs alone
towards the rectification of arsenic-mediated disorganization of membrane structural integrity, and this could
be linked with decreased ROS accumulation through reduced glutathione (GSH) repletion along with
cholesterol depletion. Moreover, activation of caspase 3 was capable of promoting aggregation of band 3 with
subsequent binding of autologous IgG and opsonization by C3b that led to phagocytosis of the exposed cells by
the macrophages. NAC–ATV treatment successfully amended these events and restored lifespan of
erythrocytes from the exposed animals almost to the control level. This work helped us to identify
intracellular membrane cholesterol enrichment and GSH depletion as the key regulatory points in arsenicmediated
erythrocyte destruction and suggested a therapeutic strategy against Fas-activated cell death
related to enhanced cholesterol and accumulation of ROS.
 
Publisher Elsevier
 
Date 2011
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/1349/1/TOXICOLOGY_AND_APPLIED_PHARMACOLOGY__250(_1)39%2D53_;2011%7B157].pdf
Biswas, Debabrata and Sen, Gargi and Sarkar, Avik and Biswas, Tuli (2011) Atorvastatin Acts Synergistically with N-acetyl Cysteine to Provide Therapeutic Advantage against Fas-Activated Erythrocyte Apoptosis during Chronic Arsenic Exposure in Rats. Toxicology and Applied Pharmacology, 250 (1). pp. 39-53.
 
Relation http://dx.doi.org/10.1016/j.taap.2010.10.002
http://www.eprints.iicb.res.in/1349/