Effects of dinuclear copper(II) complexes with 6-(benzylamino)purine derivatives on AhR and PXR dependent expression of cytochromes P450 CYP1A2 and CYP3A4 genes in primary cultures of human hepatocytes

Abstract

A series of dinuclear copper(II) complexes of the compositions [Cu 2(μ-L n ) 2(μ-Cl) 2Cl 2] ( 1, 2), [Cu 2(μ-L n ) 4Cl 2]Cl 2·2H 2O ( 3, 4) and [Cu 2(μ-L n ) 4(ClO 4) 2](ClO 4) 2· xSolv ( 5, 6; xSolv = 4MeOH for 5 and 2EtOH for 6), involving 6-(benzylamino)purine derivatives (L n ), have been evaluated with the aim to determine their possible drug interactions and their capability to induce the expression of major drug-metabolizing cytochromes P450. The above-mentioned complexes have been chosen based on the fact that substantial both in vitro (cytotoxicity, SOD-mimic) and in vivo (antidiabetic) biological activity has been found for them. As models, primary cultures of human hepatocytes and human hepatoma cells HepG2 transiently transfected with a plasmid containing dioxin-responsive element fused to the luciferase reporter gene (DRE-LUC) have been chosen. It has been found that the tested complexes 1– 6 did not significantly induce the expression of CYP1A2 and CYP3A4 mRNAs in the concentration range of 0.1–10.0 μM, in three different primary human hepatocyte cultures after 24 h of the treatment. On the other hand, the model inducers, i.e. 2,3,7,8- tetrachlorodibenzo- p-dioxin (TCDD) and rifampicin, significantly increased the levels of CYP1A2 and CYP3A4 mRNAs in all cultures. In addition, compounds 1– 6 did not transactivate DRE-LUC in transiently transfected HepG2, while TCDD strongly induced luciferase activity after 24 h of incubation. Based on the obtained results, it may be concluded that the studied dinuclear copper(II) complexes 1– 6 possess very low toxicological potential to cause drug interactions in terms of transcriptional activation of the major human cytochromes P450.