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.
A series of dinuclear copper(II) complexes of the compositions [Cu(2)(micro-L(n))(2)(micro-Cl)(2)Cl(2)] (1, 2), [Cu(2)(micro-L(n))(4)Cl(2)]Cl(2).2H(2)O (3, 4) and [Cu(2)(micro-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 0.1-10.0microM, in three different primary human hepatocyte cultures after 24h 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 24h 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.
Dvorák
Zdenek
Z
Department of Cell Biology and Genetics, Faculty of Science, Palacký University, Slechtitelů 11, 783 71 Olomouc, Czech Republic.
Vrzal
Radim
R
Starha
Pavel
P
Klanicová
Alena
A
Trávnícek
Zdenek
Z
D000328:Adult; D000368:Aged; D001593:Benzyl Compounds / Q000737:chemistry / Q000633:toxicity*; D002478:Cells, Cultured; D003300:Copper / Q000737:chemistry / Q000633:toxicity*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D000077297:Pregnane X Receptor; D011687:Purines / Q000737:chemistry / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*
D001593:Benzyl Compounds; D000077297:Pregnane X Receptor; D011687:Purines; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D011987:Receptors, Steroid; D003300:Copper; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C480551:benzylaminopurine