Bazı Kemoterapötik İlaçların İnsan Serumu Paraoksonaz-1 (PON1) Üzerindeki İnhibisyon Etkisinin Araştırılması

Yıl 2022, Cilt: 12 Sayı: 1, 297 - 305, 01.03.2022

Hakan Söyüt , Yakup Ulutaş , Ekrem Köksal

https://doi.org/10.21597/jist.978179

Öz

Kemoterapötik tedavide sıklıkla kullanılan iki ilacın (kladribin ve mitoksantron) insan serum paraoksanaz1 (PON1) enzim aktivitesi üzerindeki etkilerini in vitro inceledik. Kemoterapötik kullanılan bu ilaçlar in vitro PON1 aktivitesini azalttı. Kladribin ve mitoksantron inhibisyon mekanizması yarışmasızdır. Kladribin ve mitoksantron için IC50 değerleri sırasıyla 0.077 mM, ve 0.099 mM, olarak hesaplandı ve Ki sabitleri sırasıyla 0.057 ± 0.016 mM ve 0.067 ± 0.027 mM,olarak hesaplandı. IC50 ve Ki değerleri, kladribin’in daha güçlü inhibisyona sahip olduğunu gösterdi. Bulduğumuz sonuçlar kemoterapötik tedavide sıklıkla kullanılan bu ilaçların düşük dozlarda aynı inhibisyon mekanizmaları ile enzim aktivitesini inhibe ettiğini göstermiştir.

Anahtar Kelimeler

Paraoksonaz, inhibisyon, kladribin, mitoksantron

Investigation of Inhibition Effect of Some Chemotherapeutic Drugs on Human Serum Paraoxonase-1 (PON1)

Öz

We examined the effects of two different drugs (cladribine and mitoxantrone), which are frequently used in chemotherapeutic treatment, on human serum paraoxanase1 (PON1) enzyme activity in vitro. Chemotherapeutic drugs decreased in vitro PON1 activity. Cladribine and mitoxantrone inhibition mechanism were not competitive inhibitors. IC50 values for cladribine and mitoxantrone were calculated as 0.077 mM and 0.099 mM, respectively, and Ki constants were calculated as 0.057 ± 0.016 mM and 0.067 ± 0.027 mM, respectively. IC50 and Ki values showed that cladribine has a stronger inhibition. The results we found showed that these drugs, which are frequently used in chemotherapeutic treatment, inhibit enzyme activity with the same inhibition mechanisms at low doses.

Anahtar Kelimeler

Paraoxonase, inhibition, cladribine, mitoxantrone

Kaynakça

• Adam-Vizi V, Chinopoulos C, 2006. Bioenergetics and the formation of mitochondrial reactive oxygen species. Trends in Pharmacological Sciences, 27: 639–645.
• Alim Z, Beydemir S, 2016. Some anticancer agents act on human serum paraoxonase-1 to reduce its activity. Chemical Biology & Drug Design, 88: 188–196.
• Aviram M, Rosenblat M, 2008. Paraoxonases (PON1, PON2, PON3) analyses in vitro and in vivo in relation to cardiovascular diseases. Methods in Molecular Biology, 477: 259–276.
• Aviram M, Rosenblat M, Bisgair CL, 1998. Paraoxonase inhibits high density lipoprotein (HDL) oxidation and preserves its functions: a possible peroxidative role for paraoxonase. Journal of Clinical Investigation, 101: 2215-2257.
• Barrera G, 2012. Oxidative stress and lipid peroxidation products in cancer progression and therapy. ISRN Oncology, 2012: 137289.
• Bhattacharyya T, Nicholls SJ, Topol EJ, Zhang R, Yang X, Schmitt D, Fu X, 2008. Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. Journal of the American Medical Association, 299: 1265–1276.
• Cipollone F, Fazia ML, Mezzetti A, 2007. Oxidative stress, inflammation and atherosclerotic plaque development. International Congress Series, 1303: 35–40.
• Deakin SP, Bioletto S, Bochaton-Piallat M., James RW, 2011. HDL-associated paraoxonase-1 can redistribute to cell membranes and influence sensitivity to oxidative stress. Free Radical Biology and Medicine, 50: 102–109.
• Draganov DI, La Du, BN, 2004. Pharmacogenetics of paraoxonases: a brief review. Naunyn-Schmiedeberg's Archives of Pharmacology, 369: 78-88.
• Ferretti G, Bacchetti T, Masciangelo S, Bicchiega V, 2010. HDL-paraoxonase and membrane lipid peroxidation: a comparison between healthy and obese subjects. Obesity, 18: 1079–1084.
• Ferretti G, Bacchetti T, Sahebkar A, 2015. Effect of statin therapy on paraoxonase-1 status: a systematic review and meta-analysis of 25 clinical trials. Progress in Lipid Research, 60: 50–73.
• Furlong CE, Marsillach J, Jarvik GP, Costa LG, 2016. Paraoxonases-1, −2 and −3: what are their functions? Chemico-Biological Interactions, 259: 51–62.
• Golmanesh L, Mehrani H, Tabei M, 2008. Simple procedures for purification and stabilization of human serum paraoxonase-1. Journal of Biochemical and Biophysical Methods, 70:1037-1042.
• Gülçin İ, 2012. Antioxidant activity of food constituents: an overview. Archives of Toxicology, 86: 345-391.
• Harel M, Aharoni AI, Gaidukov L, Brumshtein B, Khersonsky O, Meged R, Dvir H, Ravelli RB, McCarthy A, Toker L, Silman I, Sussman JL, Tawfik DS, 2004. Structure and evolution of the serum paraoxonase family of detoxifying and antiatherosclerotic enymes. Nature Structural & Molecular Biology, 11: 412-419.
• Hofseth LJ, Hussain SP, Wogan GN, Harris CC, 2003. Nitric oxide in cancer and chemoprevention. Free Radical Biology and Medicine, 34: 955–968.
• Isgor MM, Beydemir S, 2010. Some cardiovascular therapeutics inhibit paraoxonase 1 (PON1) from human serum. European Journal of Pharmacology, 645: 135-142.
• Jaouad L, Milochevitch C, Khalil A, 2003. PON1 paraoxonase activity is reduced during HDL oxidation and is an indicator of HDL antioxidant capacity. Free Radical Research, 37: 77–83.
• Khan I, Gothwal A, Sharma AK, Qayum A, Singh SK, Gupta U, 2016. Biodegradable nano-architectural PEGylated approach for the improved stability and anticancer efficacy of bendamustine. International Journal of Biological Macromolecules, 92: 1242–1251.
• Khersonsky O, Tawfik DS, 2005. Structure-reactivity studies of serum paraoxonase PON1 suggest that its native activity is lactonase. Biochemistry, 44: 6371–6382.
• Kumar A, 2010. Effects of simvastatin on paraoxonase 1 (PON1) activity and oxidative stress. Asian Pacific Journal of Tropical Medicine, 3: 310-314.
• Malin R, Laaksonen R, Knuuti J, Janatuinen T, Vesalainen R, Nuutila P, Lehtimaki T, 2001. Paraoxonase genotype modifies the effect of pravastatin on high-density lipoprotein cholesterol. Pharmacogenetics, 11: 625-633.
• Marsillach J, Mackness B, Mackness M. 2008. Immunohistochemical analysis of paraoxonases-1, 2, and 3 expression in normal mouse tissues. Free Radical Biology and Medicine, 45: 146–157.
• Nagila A, Permpongpaiboon T, Tantrarongroj S, Porapakkham P, Chinwattana K, Deakin S, Porntadavity S, 2009. Effect of atorvastatin on paraoxonase1 (PON1) and oxidative status. Pharmacological Reports, 61: 892-898.
• Rozenberg O, Shih SD, Aviram M, 2005. Paraoxonase 1 (PON1) attenuates macrophage oxidative status: studies in PON1 transfected cells and in PON1 transgenic mice. Atherosclerosis, 181: 1809–1818.
• Saisho Y, Komiya N, Hirose H, 2006. Effect of valsartan, an angiotensin II receptor blocker, on markers of oxidation and glycation in Japanese type 2 diabetic subjects: blood pressure-independent effect of valsartan. Diabetes Research and Clinical Practice, 74: 201–203.
• Sinan S, Kockar F, Gencer N, Yildirim H, Arslan O, 2006. Effects of some antibiotics on paraoxonase from human serum in vitro and from mouse serum and liver in vivo. Biological and Pharmaceutical Bulletin, 29: 1559–1563.
• Spirou A, Rizos E, Liberopoulos EN, 2006. Effect of barnidipine on blood pressure and serum metabolic parameters in patients with essential hypertension: a pilot study. Journal of Cardiovascular Pharmacology and Therapeutics, 11: 256–261.
• Teiber JF, Draganov DI, La Du BN, 2003. Lactonase and Lactonizing of Human Serum Paraoxonase (PON1) and Rabbit Serum PON3. Biochemical Pharmacology, 66: 887-896.
• Türkeş C, Söyüt H, Beydemir Ş, 2014. Effect of calcium channel blockers on paraoxonase-1 (PON1) activity and oxidative stress. Pharmacological Reports, 66: 74-78.
• Türkeş C, Söyüt H, Beydemir Ş, 2016. In vitro inhibitory effects of palonosetron hydrochloride, bevacizumab and cyclophosphamide on purified paraoxonase-I (hPON1) from human serum. Environmental Toxicology and Pharmacology, 42: 252–257.