Eritrositlerde sitein transportuna azaserin'in etkisi
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Dosyalar
Tarih
2007
Yazarlar
Dergi Başlığı
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Yayıncı
Hatay Mustafa Kemal Üniversitesi
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Bu çalısmanın amacı, insan eritrositlerinde sistein giris ve çıkısı üzerine azaserinin etkisinin arastırılmasıdır. Azaserin, güçlü bir kanserojendir ve özellikle pankreasta tümör olusumuna neden olmaktadır. Glutamin kullanan enzimleri inhibe ettigi ve böylece hücrelerde de nova pürin sentezini karıstıgı bilinmektedir. Azaserin hücrelerin DNA'sında hasara neden olmakta olup, bu etkisi çogunlukla tümör olusumuna katılıcı özeligi olarak kabul edilmektedir. Azaserin bazı dokularda tümör meydana getirirken bazı dokularda tümör meydana getirmez ancak bu dokularda tümör meydana getirmesinde baska faktörlerde rol oynayabilir. Azaserin yapısal olarak glutamine benzer ve bu nedenle enzim aktiviteleri ve maddelerin membran transportu dahil birçok biyolojik olayda rol alır. Glutamin ve sistein benzer bir transport paylasım mekanizması gösterir. Buna nedenle; bir glutamin analogu olan azaserin, hücre membranından sistein transportunu etkileyebilir veya tam aksine sistein varlıgı hücrelerden azsarinin girisini ya da çıkısını etkileyebilir. Bu çalısmada eritrositler, azaserin ve sisteinin farklı konsantrasyonlarıyla muamele edilerek daha sonra zardan sistein giris ve çıkısı ölçüldü. Çalısmalarımız, azaserinin eritrosit membranlarının çift yönlü sistein transportu üzerinde bir etkiye sahip oldugunu göstermistir. Azaserin varlıgında ve yoklugunda (1.9 ± 0.14 ?mol/ml/eritrosit) hücrelere sistein girisi karsılastırıldıgında 2 mM (2.4 ± 0.07 ?mol/ml/eritrosit) azaserin varlıgında küçük bir miktarda sistein girisinin oldugu tespit edilmistir. Glutaminin sistein transportu üzerine olan etkisi de benzer olarak degerlendirilmistir. Eritrositlerden sistein çıkısında azaserin daha etkili olup, bu artıs azaserinin 0.5 mM konsantırasyonuyla baslamakta ve konsantrasyona baglı olarak artıs göstermektedir. Eritrositlerden sistein çıkıs oranı 2 mM azaserin varlıgında 0.71 ± 0.05 ?mol/ ml/ eritrosit iken azaserin yoklugunda 0.51 ± 0.01 ?mol/ ml/ eritrosit dir. Elde edilen bulgular azaserinin, azaserin/sistein degisimi mekanizmaları aracılıgıyla eritrositlere girebildigini göstermekte olup, glutamin azaserinle yapısal olarak benzerlik gösterse de sistein girisi üzerinde herhangi bir etki meydana getirmedigi tespit edilmistir. Bununla birlikte 2 mM glutamin eritrositlerden sistein çıkısını önemli derecede artırmıstır. Bulgular kanserojen bir madde olan azaserinin eritrosit membranlarında sistein degisim makanizmalarını etkiledigini göstermekte olup, azaserinin meydana getirdigi DNA hasarı ve enzim faaliyetleri üzerindeki etkilerine ek olarak azaserinin tanımlanan bu mekanizmalar ile kanser olusumuna neden olabilecegi ileri sürülebilir. Azaserin sistein degisim mekanizmalarıyla hücrelere girisi artırırken sistein varlıgını sınırlayabilir. Buda azaserinin dokularda birikmesinde ve tümör olusumunda etkin olabilir. 2007, 59 Sayfa
The objective of the present study was to investigate the effect of azaserine on cysteine influx and efflux in human erythrocytes. Azaserine is a potent carcinogen and it induces tumors especially in pancreas. Azaserine is known to inhibit glutamine utilizing enzymes and thus interfere with the de nova purine synthesis in cells. It also induces DNA damages. These effect of azaserine is readily accepted as contributors to its carcinogenity. However, subsequent induction of tumors by azaserine only in specific tissues and unresponsiveness of other tissues to azaserine suggest that other factors may also play a role in azaserine induced carcinogenesis. Azaserine structurally resembles glutamine and thus interferes with a variety biological processes including enzymatic activities and transmembrane transport of solutes. Glutamine and cyisteine have been shown to share similar transport mechanisms. In this respect azaserine, being a glutamine analog, may effect the cysteine transport acros the cell membrane or conversely cysteine availability may effect the uptake or release of azaserine. In the present study human erythrocytes were treated with different concentrations of azaserine and cysteine and then the influx and efflux of cysteine were measured. The effect of glutamine on cysteine transport was also measured in a similar way. Our results indicate that azaserine has an effect on bi-directional transport of cysteine through the erythrocyte membranes. A slight induction of cysteine influx was observed in the presence of 2 mM of azaserine (2.4 ± 0.07 ?mol/ml/erythrocyte) compared to the absence of azaserine (1.9 ± 0.14 ?mol/ml/erythrocyte). However, the effect of azaserine on cysteine efflux from erythrocytes was more pronounced and started at 0.5 mM of azaserine and then increased in a concentration dependent manner. In the presence of 2 mM of azaserine the cysteine efflux rate was 0.71 ± 0.05 ?mol/ml/erythrocyte and in the absence of azaserine the efflux rate was 0.51 ± 0.01 ?mol/ml/erythrocyte. This result suggest; that azaserine may enter in to erytrocytes by an azaserine /cysteine exchange mechanism. Glutamin did not show any effect on cysteine influx. However, 2 mM of glutamine also significantly increased the cysteine efflux from erythrocytes. Our result suggest that carcinogenic compound azaserine effects the flux of cysteine through erythrocyte membranes. We suggest that in addition to its effect on induction of DNA damages and enzymatic activities azaserine may contribute to its carcinogenity by effective cystein transport Azaserine may limit the cysteine availability as it gains into the cells in exchange with cysteine. This may also represent a mechanism by which azaserine is accumulated in tissues in which it causes carcinogenesis. 2007, 59 Pages Key words: Azaserine, Carcinogenity, Cysteine transport
The objective of the present study was to investigate the effect of azaserine on cysteine influx and efflux in human erythrocytes. Azaserine is a potent carcinogen and it induces tumors especially in pancreas. Azaserine is known to inhibit glutamine utilizing enzymes and thus interfere with the de nova purine synthesis in cells. It also induces DNA damages. These effect of azaserine is readily accepted as contributors to its carcinogenity. However, subsequent induction of tumors by azaserine only in specific tissues and unresponsiveness of other tissues to azaserine suggest that other factors may also play a role in azaserine induced carcinogenesis. Azaserine structurally resembles glutamine and thus interferes with a variety biological processes including enzymatic activities and transmembrane transport of solutes. Glutamine and cyisteine have been shown to share similar transport mechanisms. In this respect azaserine, being a glutamine analog, may effect the cysteine transport acros the cell membrane or conversely cysteine availability may effect the uptake or release of azaserine. In the present study human erythrocytes were treated with different concentrations of azaserine and cysteine and then the influx and efflux of cysteine were measured. The effect of glutamine on cysteine transport was also measured in a similar way. Our results indicate that azaserine has an effect on bi-directional transport of cysteine through the erythrocyte membranes. A slight induction of cysteine influx was observed in the presence of 2 mM of azaserine (2.4 ± 0.07 ?mol/ml/erythrocyte) compared to the absence of azaserine (1.9 ± 0.14 ?mol/ml/erythrocyte). However, the effect of azaserine on cysteine efflux from erythrocytes was more pronounced and started at 0.5 mM of azaserine and then increased in a concentration dependent manner. In the presence of 2 mM of azaserine the cysteine efflux rate was 0.71 ± 0.05 ?mol/ml/erythrocyte and in the absence of azaserine the efflux rate was 0.51 ± 0.01 ?mol/ml/erythrocyte. This result suggest; that azaserine may enter in to erytrocytes by an azaserine /cysteine exchange mechanism. Glutamin did not show any effect on cysteine influx. However, 2 mM of glutamine also significantly increased the cysteine efflux from erythrocytes. Our result suggest that carcinogenic compound azaserine effects the flux of cysteine through erythrocyte membranes. We suggest that in addition to its effect on induction of DNA damages and enzymatic activities azaserine may contribute to its carcinogenity by effective cystein transport Azaserine may limit the cysteine availability as it gains into the cells in exchange with cysteine. This may also represent a mechanism by which azaserine is accumulated in tissues in which it causes carcinogenesis. 2007, 59 Pages Key words: Azaserine, Carcinogenity, Cysteine transport
Açıklama
Anahtar Kelimeler
Biyoloji, Biology, Azaserin, Karsinogeneti, Sistein transportu
