Gadolinium-based contrast agents: in vitro paraoxonase 1 inhibition, in silico studies

BEYDEMİR Ş., TÜRKEŞ C., Yalcin A.

DRUG AND CHEMICAL TOXICOLOGY, cilt.44, sa.5, ss.508-517, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 44 Sayı: 5
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1080/01480545.2019.1620266
  • Dergi Adı: DRUG AND CHEMICAL TOXICOLOGY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, Environment Index, Food Science & Technology Abstracts, International Pharmaceutical Abstracts, MEDLINE, Veterinary Science Database
  • Sayfa Sayıları: ss.508-517
  • Anahtar Kelimeler: Paraoxonase, HDL, chromatography, inhibition, gadolinium-based contrast agents, molecular docking, NEPHROGENIC SYSTEMIC FIBROSIS, HUMAN SERUM PARAOXONASE-1, CARBONIC-ANHYDRASE, ALZHEIMERS-DISEASE, ACCURATE DOCKING, PURIFICATION, PON1, PROTEIN, DEPOSITION, ENZYME
  • Anadolu Üniversitesi Adresli: Evet

Özet

Medications show their biological effects by interaction with enzymes, which have been known to play an essential role in the pathogenesis of many diseases. Inhibition or induction of drug metabolizing enzymes has an essential place in the drug design for many kinds of diseases including cardiovascular, neurological, metabolic, and cancer. The main goal of the current study is to contribute to this growing drug design field by observing PON1-drug interactions. In recent years, the safety of gadolinium-based contrast agents (GBCAs) used in magnetic resonance imaging (MRI) has discussed. In the present study, paraoxonase 1 (PON1) enzyme was purified from human serum by simple chromatographic methods with 4095.24 EU mg(-1) protein specific activity. The inhibitory activities of gadoteric acid, gadopentetic acid, gadoxetate disodium, and gadodiamide were investigated on PON1 activity of the enzyme. IC50 values were found in the range of 51.28 +/- 0.14 to 285.80 +/- 0.96 mM. K-i constants were found as 67.95 +/- 0.60 mM, 104.97 +/- 0.96 mM, 202.33 +/- 1.75 mM, and 299.43 +/- 2.64 mM for gadoteric acid, gadopentetic acid, gadoxetate disodium, and gadodiamide, respectively. While the inhibition types are determined as competitive of gadoxetate disodium and gadodiamide by the Lineweaver-Burk curves, it was noncompetitive for other compounds. In addition, the molecular docking analyses of gadoxetate disodium and gadodiamide were carried out to understand the binding interactions on the active site of the PON1 enzyme. The structure-activity relationship (SAR) of the drugs was established on the basis of different substituents and their positions in the compounds.