Can Birsen DEMİRDÖĞEN
(Refik Saydam Hıfzıssıhha Merkezi Başkanlığı, Gıda Güvenliği ve Beslenme Araştırma Müdürlüğü, Ankara, Türkiye)
Yıl: 2010Cilt: 67Sayı: 2ISSN: 0377-9777 / 1308-2523Sayfa Aralığı: 97 - 112Türkçe

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Organofosfatlı pestisit zehirlenmeleri ve serum paraoksonaz 1 (PON1) enziminin organofosfat metabolizmasındaki rolü
Dünya Sağlık Örgütü’nün verilerine göre tüm dünyada yılda 3 milyona yakın pestisit zehirlenmesi meydana gelmekte, bunların 220.000’i ölümle sonuçlanmaktadır. Son yıllarda sıklıkla kullanılan pestisitlerden olan organofosfatlar, sinir sistemi üzerinde etki gösteren kimyasallardır. Organofosfatlar asetilkolinesteraz enzimini baskılayarak nörotoksisiteye yol açarlar. Paraoksonaz 1 (PON 1; EC 3.1.8.1) serumda yüksek dansiteli lipoprotein (HDL) üzerinde yer alan, kalsiyuma bağımlı glikoprotein yapısında bir enzimdir. Memelilerin birçok organında PON1 aktivitesi tespit edilmesine karşın, kuşlar, balıklar ve böceklerde paraoksonaz aktivitesi sıfıra yakındır. PON1’in hidrolize ettiği substratlar arasında paration, diazinon ve klorprifos gibi organofosfatlı insektisitlerin aktif formu olan toksik okson metabolitleri; sarin, ve soman gibi sinir gazları; fenil asetat gibi aromatik esterler; homogentisik asit lakton, dihidrokumarin ve homosistein tiolakton gibi birçok aromatik ve alifatik lakton ile siklik karbonatlar yer almaktadır. Organofosfatlı pestisitlerin toksikolojisi ile ilgili yapılan ilk çalışmalar düşük serum PON1 aktivitesine sahip olmanın organofosfatlı bileşiklerin akut etkilerine karşı duyarlılığı arttırdığını ortaya koymuştur. PON1’i kodlayan genin sekansının belirlenmesinin ardından, kişiler arasında enzimin aktivitesinde ve ifade edilme seviyesinde farklılıklara yol açan polimorfzmler tespit edilmesi, PON1 aktiviteleri düşük olan insanların organofosfat zehirlenmelerine karşı daha hassas olabileceğini düşündürmüştür. Son yıllarda yapılan çalışmalarda safaştırılmış PON1’in organofosfatlı pestisitlere maruz kalan hayvanlara enjekte edilmesi, dolayısı ile serum PON1 seviyesinin yapay olarak arttırılması ile klorprifos ve diazinon gibi bazı organofosfatların toksik etkilerini azaltmanın mümkün olduğu gösterilmiş, ancak bu uygulamanın paration maruziyetine karşı etkili olmadığı görülmüştür. Her ne kadar paraoksonu hidrolizleyen enzim olarak tanınsa da, PON1’in paraoksonaz aktivitesi nispeten zayıftır. Organofosfat maruziyetine karşı koruyucu olarak kullanılabilmesi için PON1’in katalitik verimi arttırılmalı ve yeterli miktarda elde edilebilmelidir. Son yıllarda protein mühendisliği yöntemleri kullanılarak PON1’in bazı amino asitlerinde değişiklikler yapılmış, bu PON1 varyantları bakteriyel sistemlerde yeterli seviyelerde ifade edilmiş ve bazı organofosfatlara karşı enzim aktivitesinde artışlar sağlanmıştır. Bu derlemede, öncelikle organofosfatların genel özelliklerine, etki mekanizmalarına ve zehirlenmelere değinilmiş, ardından PON1’in organofosfat metabolizmasındaki rolüne ve organofosfat zehirlenmelerinde antidot olarak kullanılabilmesine yönelik araştırmalardaki son gelişmeler üzerinde durulmuştur
Fen > Eczacılık > Farmakoloji ve Eczacılık
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