Two copper(II) mixed ligand complexes with dicarboxylate bridges were prepared and studied, namely [Cu2(μ-fu)(pmdien)2(H2O)2](ClO4)2 (complex No. 5) and [Cu2(μ-dtdp)(pmdien)2(H2O)2](ClO4)2 (complex No. 6), where H2fu = fumaric acid, pmdien = N,N,N',N″,N″ pentamethyldiethylenetriamine, and H2dtdp = 3,3'-dithiodipropionic acid. The copper atoms are coordinated in the same mode by the tridentate pmdien ligand and oxygen of water molecules, and they only differ in the dicarboxylate bridge. This work is focused on the study of the inhibitory effect of these potential antimicrobial drugs on the activity of the most important human liver drug-metabolizing enzymes, cytochromes P450 (CYP), especially their forms CYP2C8, CYP2C19, and CYP3A4. The obtained results allow us to estimate the probability of potential drug interactions with simultaneously administrated drugs that are metabolized by these CYP enzymes. In conclusion, the presence of adverse effects due to drug-drug interactions with concomitantly used drugs cannot be excluded, and hence, topical application may be recommended as a relatively safe approach.

• Keywords
• antibacterial activity, copper complexes, cytochromes P450, dicarboxylic acid, drug interactions, enzyme activity, inhibition,
• Publication type
• Journal Article MeSH

An evaluation of possible interactions with enzymes of drug metabolism (cytochromes P450, CYP) is an important part of studies on safety and, in general, on the properties of any drug or biologically active compound. The article is focused on the preliminary metabolic study of selected 2,6,9-trisubstituted purine kinase inhibitors with significant anticancer activities which we have developed. The compounds BP-21 and BP-117 represent strong CDK inhibitors and the compound BPA-302 was developed as selective FLT3-ITD kinase inhibitor. Here, emphasis is placed on interactions of these compounds with the nine most important forms of CYP to evaluate the possibility of inhibition of these enzymes. The possibility of their inhibitory effect was studied in vitro on selected human liver microsomal CYP enzymes. The most affected enzyme was CYP2C19. Its activity dropped to 22 % of its original value by BPA 302, to 13 % by BP-21 and to 6 % by BP-117 at the highest concentration tested (250 µmol·l(-1)). The results suggest that the metabolism of concomitantly administered drugs should not be significantly affected at lower doses. Molecular docking of BPA-302 indicated that it can bind to active site of both CYP2C19 and CYP2D6 enzymes above the heme cofactor corroborating the experimental data.

• MeSH
• Cytochrome P-450 Enzyme Inhibitors chemistry   pharmacology   MeSH
• Protein Kinase Inhibitors chemistry   pharmacology   MeSH
• Isoenzymes MeSH
• Microsomes, Liver drug effects   enzymology   MeSH
• Kinetics MeSH
• Protein Conformation MeSH
• Drug Interactions MeSH
• Humans MeSH
• Purines chemistry   pharmacology   MeSH
• Molecular Docking Simulation MeSH
• Cytochrome P-450 Enzyme System chemistry   metabolism   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cytochrome P-450 Enzyme Inhibitors MeSH
• Protein Kinase Inhibitors MeSH
• Isoenzymes MeSH
• Purines MeSH
• Cytochrome P-450 Enzyme System MeSH

Sesquiterpenes, 15-carbon compounds formed from three isoprenoid units, are the main components of plant essential oils. Sesquiterpenes occur in human food, but they are principally taken as components of many folk medicines and dietary supplements. The aim of our study was to test and compare the potential inhibitory effect of acyclic sesquiterpenes, trans-nerolidol, cis-nerolidol and farnesol, on the activities of the main xenobiotic-metabolizing enzymes in rat and human liver in vitro. Rat and human subcellular fractions, relatively specific substrates, corresponding coenzymes and HPLC, spectrophotometric or spectrofluorometric analysis of product formation were used. The results showed significant inhibition of cytochromes P450 (namely CYP1A, CYP2B and CYP3A subfamilies) activities by all tested sesquiterpenes in rat as well as in human hepatic microsomes. On the other hand, all tested sesquiterpenes did not significantly affect the activities of carbonyl-reducing enzymes and conjugation enzymes. The results indicate that acyclic sesquiterpenes might affect CYP1A, CYP2B and CYP3A mediated metabolism of concurrently administered drugs and other xenobiotics. The possible drug-sesquiterpene interactions should be verified in in vivo experiments.

• Keywords
• drug-metabolizing enzymes, farnesol, inhibition, nerolidol,
• MeSH
• Farnesol chemistry   pharmacology   MeSH
• Inhibitory Concentration 50 MeSH
• Cytochrome P-450 Enzyme Inhibitors chemistry   pharmacology   MeSH
• Liver enzymology   MeSH
• Kinetics MeSH
• Rats MeSH
• Humans MeSH
• Sesquiterpenes chemistry   pharmacology   MeSH
• Subcellular Fractions enzymology   MeSH
• Cytochrome P-450 Enzyme System metabolism   MeSH
• Xenobiotics metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Farnesol MeSH
• Cytochrome P-450 Enzyme Inhibitors MeSH
• nerolidol MeSH Browser
• Sesquiterpenes MeSH
• Cytochrome P-450 Enzyme System MeSH
• Xenobiotics MeSH

BACKGROUND: The search for an optimal experimental model in pharmacology is recently focused on (mini)pigs as they seem not only to be an alternative source of cells and tissues for xenotherapy but also an alternative species for studies on drug metabolism in man due to similarities between (mini) pig and human drug metabolizing systems. The purpose of this work is to characterize minipig liver microsomal cytochromes P450 (CYPs) by comparing their N-terminal sequences with corresponding human orthologs. RESULTS: The microsomal CYPs exhibit similar activities to their human orthologous enzymes (CYP3A4, nifedipine oxidation; 2A6, coumarin 7-hydroxylation; 2D6, bufuralol 1'-hydroxylation; 2E1, p-nitrophenol hydroxylation; and 2C9, tolbutamide hydroxylation). Specific minipig CYP (2A, 2C and 3A) enzymes were partially purified and proteins identified by immunostaining (using antibodies against the respective human CYPs) were used for N-terminal amino acid sequencing. From comparisons, it can be concluded that the sequence of the first 20 amino acids at the N-terminus of minipig CYP2A is highly similar to human CYP2A6 (70% identity). The N-terminal sequence of CYP2C shared about 50% similarity with human 2C9. The results on the minipig liver microsomal CYP3A yielded identical data with those obtained for amino acid sequences of the pig CYP3A29 showing 60% identity with human CYP3A4. CONCLUSIONS: Thus, our results further support the view that minipigs may serve as model animals in pharmacological/toxicological studies with substrates of human CYP enzymes, namely, of the CYP3A and CYP2A forms.

• MeSH
• Aryl Hydrocarbon Hydroxylases chemistry   metabolism   MeSH
• Cytochrome P-450 CYP3A MeSH
• Species Specificity MeSH
• Microsomes, Liver enzymology   MeSH
• Humans MeSH
• Swine, Miniature MeSH
• Sequence Analysis, Protein MeSH
• Steroid Hydroxylases chemistry   metabolism   MeSH
• Substrate Specificity MeSH
• Cytochrome P-450 Enzyme System chemistry   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Names of Substances
• Aryl Hydrocarbon Hydroxylases MeSH
• CYP3A protein, human MeSH Browser
• CYP3A4 protein, human MeSH Browser
• Cytochrome P-450 CYP3A MeSH
• cytochrome P-450 CYP2C subfamily MeSH Browser
• steroid hormone 7-alpha-hydroxylase MeSH Browser
• Steroid Hydroxylases MeSH
• Cytochrome P-450 Enzyme System MeSH