Inhibitory Effects of Bendamustine on Human Serum Paraoxonase-1 (hPON1)

Öz

hPON1 is an ester hydrolase associated with HDL and having a molecular mass of 43-45 kDa. It is synthesized in the liver. It hydrolyzes organophosphate agents and nerve gases. It plays a protective role against oxidation of LDL and formation of lipid peroxides and bacterial endotoxins. The fact that oxidation of LDL constitutes the initial stage of the atherosclerosis process demonstrates the importance of hPON1 antioxidant properties. Many epidemiological studies have shown an inverse relationship between HDL cholesterol levels and cardiovascular events. It is known that high serum HDL-cholesterol and low LDL-cholesterol levels are protective against the development of coronary heart disease and atherosclerosis. Therefore, hPON1 is a component of HDL, thus contributing to the protective role of HDL in coronary artery disease. In this research, we investigated the inhibition effects of bendamustine on hPON1 enzyme activity in the human serum in vitro conditions.

Anahtar Kelimeler

• bendamustine
• inhibition
• Paraoxonase

İnsan Serum Paraoksonaz-1 (hPON1) Üzerine Bendamustin İnhibisyon Etkisi

Öz

hPON1, HDL ile ilişkili ve 43-45 kDa'lık bir moleküler kütleye sahip olan bir ester hidrolazdır. Karaciğerde sentezlenir. Organofosfat ajanlarını ve sinir gazlarını hidrolize eder. LDL'nin oksidasyonuna ve lipit peroksitlerin ve bakteriyel endotoksinlerin oluşumuna karşı koruyucu bir rol oynar. LDL'nin oksidasyonunun ateroskleroz sürecinin başlangıç aşamasını oluşturması, hPON1 antioksidan özelliklerinin önemini göstermektedir. Birçok epidemiyolojik çalışma HDL kolesterol düzeyleri ile kardiyovasküler olaylar arasında ters bir ilişki olduğunu göstermiştir. Yüksek serum HDL-kolesterol ve düşük LDL-kolesterol seviyelerinin koroner kalp hastalığı ve ateroskleroz gelişimine karşı koruyucu olduğu bilinmektedir. Bu nedenle, hPON1 bir HDL bileşenidir, bu nedenle koroner arter hastalığında HDL'nin koruyucu rolüne katkıda bulunur. Bu araştırmada, in vitro koşullarda insan serumunda hPON1 enzim aktivitesi üzerine bendamustin kemoterapik ilacının inhibisyon etkisini araştırdık.

Anahtar Kelimeler

• Paraoksanaz
• inhibisyon
• bendamustin

Kaynakça

1. 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.
2. 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.
3. Barrera G, 2012. Oxidative stress and lipid peroxidation products in cancer progression and therapy. ISRN Oncology, 2012: 137289.
4. 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.
5. 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.
6. 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
7. 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
8. Furlong CE, Marsillach J, Jarvik GP, Costa LG, 2016. Paraoxonases-1, −2 and −3: what are their functions? Chemico-Biological Interactions, 259: 51–62.

9. 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.
10. 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.
11. Kumar A, 2010. Effects of simvastatin on paraoxonase 1 (PON1) activity and oxidative stress. Asian Pacific Journal of Tropical Medicine, 3: 310-314.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.