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- Title
Vascular Toxicity Risk Assessment of MC18 and MC70, Novel Potential Diagnostic Tools for In Vivo PET Studies.
- Authors
Fusi, Fabio; Durante, Miriam; Sticozzi, Claudia; Frosini, Maria; Perrone, Maria G.; Colabufo, Nicola A.; Saponara, Simona
- Abstract
The P-glicoprotein (P-gp) inhibitor MC18 has been recently proposed as a valuable PET tracer to measure P-gp expression in vivo. The aim of this study was to evaluate the toxic hazard towards the vasculature of MC18 along with the structurally related and more potent P-gp inhibitor MC70. Their effects on A7r5 and EA.hy926 cells viability, on the mechanical activity of fresh and cultured rat aorta rings as well as on Cav1.2 channel current ( ICa1.2) of A7r5 cells were studied. At concentrations >10 μM, MC18 and MC70 decreased cell viability causing evident morphological changes. In fresh rat aorta rings, both compounds (0.1-100 μM) antagonized phenylephrine-induced contraction in a concentration-dependent manner, with IC50 values in the range of 1.67-14.49 μM, whereas only MC18 caused a concentration-dependent decrease of the 60 mM K+ (K60)-induced responses. In rings cultured for 7 days with both compounds (1-10 μM), 10 μM MC70 significantly reduced, while 10 μM MC18 completely prevented the contractile response to both phenylephrine and K60. MC18 and MC70 (0.1-100 μM) inhibited ICa1.2 in a concentration-dependent manner with IC50 values of 16.81 and 32.13 μM, respectively. These findings demonstrate that MC18-induced vascular effects took place at concentrations that are at least three orders of magnitude higher than those (≤10 nM) allowing in vivo measurement of P-gp expression. Thus, MC18, and possibly MC70, can be considered promising PET tools for in vivo P-gp quantification.
- Subjects
TOXICITY testing; PROTEIN analysis; HEALTH risk assessment; VASCULAR diseases; PROTEIN expression; TRACERS (Biology)
- Publication
Basic & Clinical Pharmacology & Toxicology, 2017, Vol 120, Issue 5, p434
- ISSN
1742-7835
- Publication type
Article
- DOI
10.1111/bcpt.12719