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.
Department of Cell Biology and Genetics, Faculty of Science, Palacký University, Slechtitelů 11, 783 71 Olomouc, Czech Republic.
Zdenek
Z
Dvorák
Radim
R
Vrzal
Pavel
P
Starha
Alena
A
Klanicová
Zdenek
Z
Trávnícek
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