ABC transporters: circadian rhythms and sex-related differences

Yıl 2013, Cilt: 3 Sayı: 1, 1 - 13, 29.01.2014

Zeliha Pala Kara Narin Öztürk Dilek Öztürk Alper Okyar

Öz

ABC (ATP-binding cassette) transporter superfamily contains membrane proteins transporting substrates across the plasma membrane including drugs, xenobiotics and endogenous compounds. ABC proteins are ATP-dependent primary active transporters that pump substrates across the membranes. In addition to the expression of ABC transporters in intestinal segments, liver and kidney which are responsible for absorption, metabolism and elimination, these are also expressed in other important tissues such as brain and heart. P-glycoprotein (P-gp), multidrug resistance associated proteins (MRPs) and breast cancer resistance protein (BCRP) , the important members of ABC superfamily, play significant role in pharmacokinetics and detoxification of drugs and drug metabolites facilitating intestinal secretion, and excretion of drugs into the bile and urine in liver and kidney respectively. In addition to expression of ABC proteins in healthy tissues, they are also expressed in tumor cells, and cause multidrug resistance (MDR) by extruding antineoplastic drugs out of tumor cells and reducing the accumulation of drugs in tumor tissues, thus result in failure of chemotherapy. Expression of ABC transporters in healthy tissues shows circadian rhythm, and activities of these transporters increase and decrease depending on the time of day. Thus, the efficacy and toxicity of drugs transported by ABC transporters change depending on application time of drugs. Additionally, sex-related differences in ABC transporters, not only for drug metabolizing enzymes, are seen as an important factor in the variation of drug effectiveness and drug-induced response. Intra-day and gender-related changes in the functional activity of transporters are important parameters that may change the pharmacological effects and toxicity of drugs.

Key words: ABC transporters, P-gp, BCRP, MRP2, circadian rhythm, sex-related differences, drug resistance, MDR

Anahtar Kelimeler

ABC transporters, P-gp, BCRP, MRP2, circadian rhythm, sex-related differences, drug resistance, MDR

ABC taşıyıcı proteinleri: Sirkadiyan ritimler ve cinsiyete bağlı farklılıklar

Öz

ABC (ATP-binding cassette) taşıyıcı ailesi çeşitli ilaçların, ksenobiyotiklerin ve endojen bileşiklerin, membranlardan taşınmasını sağlayan proteinlerden oluşmaktadır. ABC proteinleri substratlarını membranlardan pompalayan, ATP’ye bağımlı olarak çalışan primer aktif taşıyıcılardır. Bunların bağırsak segmentleri, karaciğer, böbrek gibi ilaç emilimi, metabolizması ve atılımından sorumlu organların yanı sıra, beyin ve kalp gibi diğer önemli dokulardaki varlığı da bilinmektedir. ABC taşıyıcı ailesinin önemli üyeleri olan P-glikoprotein (P-gp), çoklu ilaç rezistans bağlantılı proteinler (MRP’ler) ve meme kanseri rezistans proteini (BCRP), ilaçların bağırsaklardan atılımında rol oynamakta; karaciğer ve böbreklerde ise ilaçların sırasıyla safra ve idrar ile atılımlarını kolaylaştırmaktadır. Bu nedenle, ABC taşıyıcılarının ilaç ve ilaç metabolitlerinin farmakokinetiğinde ve detoksifikasyonunda önemli görev üstlendiği bilinmektedir. ABC proteinleri, sağlıklı dokuların yanı sıra birçok tümör dokusunda eksprese olmaktadır. Bu taşıyıcılar, antineoplastik ilaçları tümör hücrelerinden dışarı atarak, ilacın tümör dokusunda toplanmasını engellemekte ve böylece uygulanan kemoterapinin başarısız olmasına yol açmaktadır. Çoklu ilaç direnci (MDR; multidrug resistance) olarak bilinen bu durum kanser tedavisinde önemli bir sorun olarak önemini korumaktadır. Sağlıklı dokularda ABC taşıyıcılarının ekspresyonları sirkadiyan ritim göstermekte ve günün zamanına göre etkinlikleri artmakta veya azalmaktadır. Bu durum ABC taşıyıcıları ile taşınan ilaçların etkinlikleri ve toksisitelerinde uygulama zamanına bağlı olarak farklılıklara neden olmakta ve özellikle ABC taşıyıcıları için substrat olan antineoplastik ilaçlar için önem arz etmektedir. Ek olarak, ilaç etkinliğinin ve ilaca bağlı cevabın değişkenlik göstermesinde önemli bir faktör olarak görülen cinsiyete bağlı değişiklikler, sadece ilaç metabolizmasından sorumlu enzimler için değil, taşıyıcı proteinler için de gösterilmiştir. Taşıyıcıların fonksiyonel aktivitelerinde gün içi ve cinsiyete bağlı değişikliklerin oluşması ilacın farmakolojik etkilerini ve toksisitesini değiştirebilen önemli parametreler olarak görülmektedir.

Anahtar Kelimeler : ABC taşıyıcı proteinleri, P-gp, BCRP, MRP2, sirkadiyan ritim, cinsiyete bağlı farklılıklar, ilaç rezistansı, MDR

Anahtar Kelimeler

ABC taşıyıcı proteinleri, P-gp, BCRP, MRP2, sirkadiyan ritim, cinsiyete bağlı farklılıklar, ilaç rezistansı, MDR

Kaynakça

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