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S-allyl Cysteine in Combination with Clotrimazole Downregulates Fas Induced Apoptotic Events in Erythrocytes of Mice exposed to Lead

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Title S-allyl Cysteine in Combination with Clotrimazole Downregulates Fas Induced Apoptotic Events in Erythrocytes of Mice exposed to Lead
 
Creator Mandal, Samir
Mukherjee, Sudip
Dutta Chowdhury, Kaustav
Sarkar, Avik
Basu, Kankana
Paul, Soumosish
Karmakar, Debasish
Chatterjee, Mahasweta
Biswas, Tuli
Sadhukhan, Gobinda Chandra
Sen, Gargi
 
Subject Cell Biology & Physiology
 
Description Background: Chronic lead (Pb2+) exposure leads to the reduced lifespan of erythrocytes. Oxidative stress and
K+ loss accelerate Fas translocation into lipid raft microdomains inducing Fas mediated death signaling in
these erythrocytes. Pathophysiological-based therapeutic strategies to combat against erythrocyte death
were evaluated using garlic-derived organosulfur compounds like diallyl disulfide (DADS), S allyl cysteine
(SAC) and imidazole based Gardos channel inhibitor clotrimazole (CLT).
Methods: Morphological alterations in erythrocytes were evaluated using scanning electron microscopy.
Events associated with erythrocyte death were evaluated using radio labeled probes, flow cytometry and activity
gel assay. Mass spectrometry was used for detection of GSH–4-hydroxy-trans-2-nonenal (HNE) adducts.
Fas redistribution into the lipid rafts was studied using immunoblotting technique and confocal
microscopy.
Results: Combination of SAC and CLT was better than DADS and CLT combination and monotherapy with
these agents in prolonging the survival of erythrocytes during chronic Pb2+ exposure. Combination therapy
with SAC and CLT prevented redistribution of Fas into the lipid rafts of the plasma membrane and downregulated
Fas-dependent death events in erythrocytes of mice exposed to Pb2+.
Conclusion and general significance: Ceramide generation was a critical component of Fas receptor-induced
apoptosis, since inhibition of acid sphingomyelinase (aSMase) interfered with Fas-induced apoptosis during
Pb2+ exposure. Combination therapy with SAC and CLT downregulated apoptotic events in erythrocytes by
antagonizing oxidative stress and Gardos channel that led to suppression of ceramide-initiated Fas aggregation
in lipid rafts. Hence, combination therapy with SAC and CLT may be a potential therapeutic option for
enhancing the lifespan of erythrocytes during Pb2+ toxicity.
 
Publisher Elsevier
 
Date 2012
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/1494/1/BIOCHIMICA_ET_BIOPHYSICA_ACTA%2DGENERAL_SUBJECTS___1820(_1)_9%2D23;2012[81].pdf
Mandal, Samir and Mukherjee, Sudip and Dutta Chowdhury, Kaustav and Sarkar, Avik and Basu, Kankana and Paul, Soumosish and Karmakar, Debasish and Chatterjee, Mahasweta and Biswas, Tuli and Sadhukhan, Gobinda Chandra and Sen, Gargi (2012) S-allyl Cysteine in Combination with Clotrimazole Downregulates Fas Induced Apoptotic Events in Erythrocytes of Mice exposed to Lead. BBA - Biochimica et Biophysica Acta, 1820 (1). 09-23.
 
Relation http://dx.doi.org/10.1016/j.bbagen.2011.09.019
http://www.eprints.iicb.res.in/1494/