Sirkadiyan ritim ve sitokrom p450 enzimleri

Sirkadiyan ritim, ilaç ve ksenobiyotiklerin emilme, dağılma, metabolizma ve atılma kinetiğinde görev alan detoksifikasyon enzimlerini, biyokimyasal ve fizyolojik yolaklar üzerinden etkiler. Bu enzimler arasında önemli olan sitokrom P450 (CYP-450) ailesinden, CYP2 (CYP2A1/4/5, CYP2B1/2/10, CYP2C6/50, CYP2E1), CYP3 (CYP3A4/11), CYP4A3, CYP8B7A, CYP9, CYP7, CYP17 ve detoksifikasyon proteinlerinin birçoğunun transkripsiyonel aktivasyonunda rol oynayan nükleer reseptörlerden pregnane-X reseptör (PXR, NR112), konstitutif adrostan reseptörü (constitutive androstane receptor- CAR, NR113), peroksizome proliferatör-etkinleyici reseptör alfa (peroxisome proliferator-actived receptor alpha- PPAR), retinoik asit reseptör (retinoic acid receptor- RAR), related orphan reseptörü (related orphan receptor- ROR) ve RER-ERBα’nın moleküler regülasyonun sirkadiyan ritim tarafından düzenlendiği çeşitli çalışmalarda bildirilmiştir. Biyolojik saati etkileyen ve hepatik CYP450 monoksijenazları tarafından metabolize edilen melatonin de bu enzimlerin regülasyonunu etkilemektedir. Bu nedenle, kronoterapi ve kronotoksisite bakımından önem taşıyan, ilaç ve zehirlerin etkinliği ve toksisitesindeki gün içerisindeki farklılıkların, büyük çoğunlukla karaciğerde bulunan ilaç metabolizmasındaki sirkadiyan değişikliklerden kaynaklandığı söylenebilir ve özellikle deneysel çalışmalarda da daha doğru sonuçların alınabilmesi için, bu durum mutlaka dikkate alınmalıdır.

Circadian rhythm and cytochrome p450 enzymes

Circadian rhythm has an effect on the response of the metabolism, distribution, absorption and elimination kinetics of drug and xenobiotic metabolism through biochemical and physiological pathways of detoxification enzymes. Among those enzymes, cytochrome P450 enzymes (CYP-450); CYP2 (CYP2A1/4/5, CYP2B1/2/10, CYP2C6/50, CYP2E1), CYP3 (CYP3A4/11), CYP4A3, CYP8B7A, CYP9, CYP7, CYP17 and the transcriptional activators of these enzymes through nuclear receptors, such as pregnane-X receptor (PXR, NR112), constitutive adrostane receptor (CAR, NR113), peroxisome proliferator-activated receptor alpha (PPAR), retinoic acid receptor (RAR), related orphan receptor (ROR) and RER-ERBα, have been shown to follow circadian rhytmicity in several studies. Melatonin which is metabolized by these hepatic CYP450 monooxy-genases, affects the biological clock and the regulation of these enzymes. Therefore, it could be stated that the circadian variation of these detoxification enzymes affects the availability and toxicity of drugs and xenobiotics which influence the chronotherapeutical and chronotoxicity approaches rather than the classical one, should also be considered in future experimental studies for obtaining more reliable outcomes.

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