Polycyclic aromatic hydrocarbons (PAHs), including the Group 1 human carcinogen benzo[a]pyrene (BaP), are produced by the incomplete combustion of organic matter and thus are present in tobacco smoke, charbroiled food and diesel exhaust. The nematode Caenorhabditis elegans is an established model organism, however it lacks the genetic components of the classical mammalian cytochrome P450 (CYP)-mediated BaP-diol-epoxide metabolism pathway. We therefore introduced human CYP1A1 or CYP1A2 together with human epoxide hydrolase (EPHX) into the worm genome by Mos1-mediated Single Copy Insertion (MosSCI) and evaluated their response to BaP exposure via toxicological endpoints. Compared to wild-type control, CYP-humanised worms were characterised by an increase in pharyngeal pumping rate and a decrease in volumetric surface area. Furthermore, BaP exposure reduced reproductive performance, as reflected in smaller brood size, which coincided with the downregulation of the nematode-specific major sperm protein as determined by transcriptomics (RNAseq). BaP-mediated reproductive toxicity was exacerbated in CYP-humanised worms at higher exposure levels. Collagen-related genes were downregulated in BaP-exposed animals, which correlate with the reduction in volumetric size. Whole genome DNA sequencing revealed a higher frequency of T > G (A > C) base substitution mutations in worms expressing human CYP1A1;EPHX which aligned with an increase in DNA adducts identified via an ELISA method (but not classical 32P-postlabelling). Overall, the CYP-humanised worms provided new insights into the value of genome-optimised invertebrate models by identifying the benefits and limitations within the context of the (3Rs) concept which aims to replace, reduce and refine the use of animals in research.

• Klíčová slova
• Benzo[a]pyrene, CYP1A1, CYP1A2, Caenorhabditis elegans, DNA adducts, Mutational patterns, RNAseq,
• MeSH
• benzopyren * toxicita   MeSH
• Caenorhabditis elegans * genetika   účinky léků   MeSH
• cytochrom P-450 CYP1A1 * genetika   metabolismus   MeSH
• cytochrom P-450 CYP1A2 * genetika   metabolismus   MeSH
• geneticky modifikovaná zvířata MeSH
• karcinogeneze MeSH
• lidé MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzopyren * MeSH
• CYP1A1 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP1A1 * MeSH
• cytochrom P-450 CYP1A2 * MeSH

The endoplasmic reticulum is organized into ordered regions enriched in cholesterol and sphingomyelin, and disordered microdomains characterized by more fluidity. Rabbit CYP1A1 and CYP1A2 localize into disordered and ordered microdomains, respectively. Previously, a CYP1A2 chimera containing the first 109 amino acids of CYP1A1 showed altered microdomain localization. The goal of this study was to identify specific residues responsible for CYP1A microdomain localization. Thus, CYP1A2 chimeras containing substitutions from homologous regions of CYP1A1 were expressed in HEK 293T/17 cells, and the localization was examined after solubilization with Brij 98. A CYP1A2 mutant with the three amino acids from CYP1A1 (VAG) at positions 27 to 29 of CYP1A2 was generated that showed a distribution pattern similar to those of CYP1A1/1A2 chimeras containing both the first 109 amino acids and the first 31 amino acids of CYP1A1 followed by remaining amino acids of CYP1A2. Similarly, the reciprocal substitution of three amino acids from CYP1A2 (AVR) into CYP1A1 resulted in a partial redistribution of the chimera into ordered microdomains. Molecular dynamic simulations indicate that the positive charges of the CYP1A1 and CYP1A2 linker regions between the N termini and catalytic domains resulted in different depths of immersion of the N termini in the membrane. The overlap of the distribution of positively charged residues in CYP1A2 (AVR) and negatively charged phospholipids was higher in the ordered than in the disordered microdomain. These findings identify three residues in the CYP1AN terminus as a novel microdomain-targeting motif of the P450s and provide a mechanistic explanation for the differential microdomain localization of CYP1A.

• Klíčová slova
• CYP1A1, CYP1A2, cytochrome P450, membrane charge depth, membrane protein, microdomain localization, microdomain-targeting motif, protein chimera, protein-lipid interaction, structure-function,
• MeSH
• cytochrom P-450 CYP1A1 * genetika   metabolismus   chemie   MeSH
• cytochrom P-450 CYP1A2 * metabolismus   genetika   chemie   MeSH
• endoplazmatické retikulum metabolismus   MeSH
• HEK293 buňky MeSH
• králíci MeSH
• lidé MeSH
• membránové mikrodomény metabolismus   genetika   MeSH
• proteinové domény MeSH
• sekvence aminokyselin MeSH
• simulace molekulární dynamiky MeSH
• substituce aminokyselin MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cytochrom P-450 CYP1A1 * MeSH
• cytochrom P-450 CYP1A2 * MeSH

Objectives Cytochromes P450 play a role in human drugs metabolic pathways and their genes are among the most variable in humans. The aim of this study was to analyze genotype frequencies of five common polymorphisms of cytochromes P450 in Roma/Gypsy and Czech (non-Roma) population samples with Czech origin. Methods Roma/Gypsy (n=302) and Czech subjects (n=298) were genotyped for CYP1A2 (rs762551), CYP2A6 (rs4105144), CYP2B6 (rs3745274) and CYP2D6 (rs3892097; rs1065852) polymorphisms using PCR-RFLP or Taqman assay. Results We found significant allelic/genotype differences between ethnics in three genes. For rs3745274 polymorphism, there was increased frequency of T allele carriers in Roma in comparison with Czech population (53.1 vs. 43.7%; p=0.02). For rs4105144 (CYP2A6) there was higher frequency of T allele carriers in Roma in comparison with Czech population (68.7 vs. 49.8%; p<0.0001). For rs3892097 (CYP2D6) there was more carriers of the A allele between Roma in comparison with Czech population (39.2 vs. 38.2%; p=0.048). Genotype/allelic frequencies of CYP2D6 (rs1065852) and CYP1A2 (rs762551) variants did not significantly differ between the ethnics. Conclusions There were significant differences in allelic/genotype frequencies of some, but not all cytochromes P450 polymorphisms between the Czech Roma/Gypsies and Czech non-Roma subjects.

• Klíčová slova
• Czech majority, Roma/Gypsy, cytochromes P450, polymorphism,
• MeSH
• cytochrom P-450 CYP1A2 genetika   metabolismus   MeSH
• cytochrom P-450 CYP2D6 genetika   metabolismus   MeSH
• cytochrom P450 CYP2A6 genetika   metabolismus   MeSH
• cytochrom P450 CYP2B6 genetika   metabolismus   MeSH
• dospělí MeSH
• genotyp MeSH
• lidé MeSH
• polymorfismus genetický genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• CYP1A2 protein, human MeSH Prohlížeč
• CYP2A6 protein, human MeSH Prohlížeč
• CYP2B6 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP1A2 MeSH
• cytochrom P-450 CYP2D6 MeSH
• cytochrom P450 CYP2A6 MeSH
• cytochrom P450 CYP2B6 MeSH

The selection of a suitable combination of reference genes (RGs) for data normalization is a crucial step for obtaining reliable and reproducible results from transcriptional response analysis using a reverse transcription-quantitative polymerase chain reaction. This is especially so if a three-dimensional multicellular model prepared from liver tissues originating from biologically diverse human individuals is used. The mRNA and miRNA RGs stability were studied in thirty-five human liver tissue samples and twelve precision-cut human liver slices (PCLS) treated for 24 h with dimethyl sulfoxide (controls) and PCLS treated with β-naphthoflavone (10 µM) or rifampicin (10 µM) as cytochrome P450 (CYP) inducers. Validation of RGs was performed by an expression analysis of CYP3A4 and CYP1A2 on rifampicin and β-naphthoflavone induction, respectively. Regarding mRNA, the best combination of RGs for the controls was YWHAZ and B2M, while YWHAZ and ACTB were selected for the liver samples and treated PCLS. Stability of all candidate miRNA RGs was comparable or better than that of generally used short non-coding RNA U6. The best combination for the control PCLS was miR-16-5p and miR-152-3p, in contrast to the miR-16-5b and miR-23b-3p selected for the treated PCLS. Our results showed that the candidate RGs were rather stable, especially for miRNA in human PCLS.

• Klíčová slova
• RT-qPCR, human liver, mRNA, miRNA, precision-cut liver slices, reference gene,
• MeSH
• beta-2-mikroglobulin genetika   metabolismus   MeSH
• beta-naftoflavon farmakologie   MeSH
• cytochrom P-450 CYP1A2 genetika   metabolismus   MeSH
• cytochrom P-450 CYP3A genetika   metabolismus   MeSH
• dimethylsulfoxid farmakologie   MeSH
• dospělí MeSH
• játra účinky léků   metabolismus   MeSH
• kvantitativní polymerázová řetězová reakce normy   MeSH
• lidé středního věku MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• mikro RNA genetika   metabolismus   MeSH
• proteiny 14-3-3 genetika   metabolismus   MeSH
• referenční standardy MeSH
• rifampin farmakologie   MeSH
• senioři MeSH
• stanovení celkové genové exprese normy   MeSH
• systém (enzymů) cytochromů P-450 farmakologie   MeSH
• transkriptom MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• B2M protein, human MeSH Prohlížeč
• beta-2-mikroglobulin MeSH
• beta-naftoflavon MeSH
• CYP1A2 protein, human MeSH Prohlížeč
• CYP3A4 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP1A2 MeSH
• cytochrom P-450 CYP3A MeSH
• dimethylsulfoxid MeSH
• messenger RNA MeSH
• mikro RNA MeSH
• proteiny 14-3-3 MeSH
• rifampin MeSH
• systém (enzymů) cytochromů P-450 MeSH
• YWHAZ protein, human MeSH Prohlížeč

Stevia rebaudiana Bertoni is a herb known for the high content of natural sweeteners in its leaves. Its main secondary metabolite stevioside is used as non-caloric sweetener. No information, however, is available on whether stevioside or steviol interact with drug-metabolizing enzymes and pose the potential risk of food-drug interactions. Similarly, data are lacking on the interactions of steviol and stevioside with key nuclear receptors controlling the expression of the main drug metabolizing enzymes. We studied the interactions of steviol and stevioside with the pregnane X (PXR), vitamin D (VDR), constitutive androstane (CAR), farnesoid X (FXR), glucocorticoid (GR) and aryl hydrocarbon (AHR) receptors, which control expression of genes of xenobiotic metabolism. In addition, the inhibitory activities of steviol and stevioside towards the major cytochrome P450 enzymes CYP3A4, CYP2C9, CYP2D6, CYP1A2 and CYP2B6 were evaluated in vitro. We found that steviol moderately activated the PXR and AHR, resulting in the induction of their target genes including CYP3A4 and CYP1A2 in primary human hepatocytes. A weak inhibition of CYP3A4 and CYP2C9 with steviol was also found. Our results provide mechanistic data indicating that stevioside and stevia sweeteners may have the potential to induce food-drug interactions, a finding that warrants future prospective clinical investigation.

• Klíčová slova
• Drug metabolism, Food-drug interactions, Nuclear receptors, Steviol, Stevioside,
• MeSH
• cytochrom P-450 CYP1A2 genetika   metabolismus   MeSH
• diterpeny kauranové metabolismus   MeSH
• hepatocyty metabolismus   MeSH
• kultivované buňky MeSH
• lidé MeSH
• metabolická inaktivace MeSH
• pregnanový X receptor MeSH
• receptory aromatických uhlovodíků genetika   metabolismus   MeSH
• rostlinné extrakty metabolismus   MeSH
• senioři MeSH
• sladidla metabolismus   MeSH
• steroidní receptory genetika   metabolismus   MeSH
• Stevia chemie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cytochrom P-450 CYP1A2 MeSH
• diterpeny kauranové MeSH
• pregnanový X receptor MeSH
• receptory aromatických uhlovodíků MeSH
• rostlinné extrakty MeSH
• sladidla MeSH
• steroidní receptory MeSH
• steviol MeSH Prohlížeč

Natural polyphenol resveratrol (trihydroxystilbene) is a partial agonist of human aryl hydrocarbon receptor AhR, thereby, displaying a plethora of biological effects. Biological activities of metoxylated and hydroxylated stilbenes were studied in the past. The aim of the current study was to describe the effects of 13 different hydroxy- and methoxystilbenes, including their cis/trans isomers on the transcriptional activity of AhR and the expression of CYP1A genes in hepatic cancer cells HepG2 and in primary human hepatocytes. Techniques of gene reporter assays, qRT-PCR, Simple Western blotting by Sally Sue™ and electrophoretic mobility shift assay EMSA were employed. All compounds activated AhR, but their efficacies, potencies and dose-response profiles differed substantially. The strongest activators of AhR and inducers of CYP1A1 in HepG2 cells were DMU-212 ((E)-3,4,5,4´-tetramethoxystilbene), trans-piceatannol, cis-piceatannol, trans-trismethoxyresveratrol and trans-pinostilbene. While DMU-212 and trans-trismethoxyresveratrol also induced CYP1A1 and CYP1A2 in primary human hepatocytes, the effects of trans-piceatannol, cis-piceatannol and trans-pinostilbene weaned off. On the other hand, trans-4-methoxystilbene was strong CYP1A inducer in hepatocytes but not in HepG2 cells. Differences between effects of stilbenes in HepG2 cells and human hepatocytes are probably due to the extensive phase I and phase II xenobiotic metabolism in human hepatocytes. The data obtained may be of toxicological relevance.

• Klíčová slova
• AhR, CYP1A1, CYP1A2, Cytochrome P450, Hepatocytes, Stilbene derivatives,
• MeSH
• buňky Hep G2 účinky léků   MeSH
• cytochrom P-450 CYP1A1 genetika   MeSH
• cytochrom P-450 CYP1A2 genetika   MeSH
• dospělí MeSH
• hepatocyty účinky léků   MeSH
• induktory cytochromu P450 CYP1A2 chemie   farmakologie   MeSH
• isomerie MeSH
• kultivované buňky MeSH
• lidé středního věku MeSH
• lidé MeSH
• receptory aromatických uhlovodíků genetika   metabolismus   MeSH
• regulace genové exprese účinky léků   MeSH
• resveratrol MeSH
• senioři MeSH
• stilbeny chemie   farmakologie   MeSH
• transkripční faktory bHLH genetika   metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 3,4,5,4'-tetramethoxystilbene MeSH Prohlížeč
• AHR protein, human MeSH Prohlížeč
• CYP1A1 protein, human MeSH Prohlížeč
• CYP1A2 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP1A1 MeSH
• cytochrom P-450 CYP1A2 MeSH
• induktory cytochromu P450 CYP1A2 MeSH
• pinostilbene MeSH Prohlížeč
• receptory aromatických uhlovodíků MeSH
• resveratrol MeSH
• stilbeny MeSH
• transkripční faktory bHLH MeSH

The effects of four copper(II) mixed-ligand complexes [Cu(qui1)(L)]NO3·H2O (1-3) and [Cu(qui2)(phen)]NO3 (4), where qui1=2-phenyl-3-hydroxy-4(1H)-quinolinone, Hqui2=2-(4-amino-3,5-dichlorophenyl)-N-propyl-3-hydroxy-4(1H)-quinolinone-7-carboxamide, L=1,10-phenanthroline (phen) (1), 5-methyl-1,10-phenanthroline (mphen) (2), bathophenanthroline (bphen) (3), on transcriptional activities of steroid receptors, nuclear receptors and xenoreceptors have been studied. The complexes (1-4) did not influence basal or ligand-inducible activities of glucocorticoid receptor, androgen receptor, thyroid receptor, pregnane X receptor and vitamin D receptor, as revealed by gene reporter assays. The complexes 1 and 2 dose-dependently induced luciferase activity in stable gene reporter AZ-AhR cell line, and this induction was reverted by resveratrol, indicating involvement of aryl hydrocarbon receptor (AhR) in the process. The complexes 1, 2 and 3 induced CYP1A1 mRNA in LS180 cells and CYP1A1/CYP1A2 in human hepatocytes through AhR. Electrophoretic mobility shift assay EMSA showed that the complexes 1 and 2 transformed AhR in its DNA-binding form. Collectively, we demonstrate that the complexes 1 and 2 activate AhR and induce AhR-dependent genes in human hepatocytes and cancer cell lines. In conclusion, the data presented here might be of toxicological importance, regarding the multiple roles of AhR in human physiology and pathophysiology.

• Klíčová slova
• Copper(II) complexes, Cytochrome P450, Human hepatocytes, Nuclear receptors, Xenobiotics,
• MeSH
• aktivace transkripce účinky léků   MeSH
• cytochrom P-450 CYP1A1 biosyntéza   genetika   MeSH
• cytochrom P-450 CYP1A2 biosyntéza   genetika   MeSH
• dospělí MeSH
• dusičnany toxicita   MeSH
• enzymová indukce MeSH
• fenantroliny toxicita   MeSH
• genetická transkripce účinky léků   MeSH
• hepatocyty účinky léků   enzymologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• ligandy MeSH
• měď toxicita   MeSH
• messenger RNA biosyntéza   genetika   MeSH
• MFC-7 buňky MeSH
• primární buněčná kultura MeSH
• receptory aromatických uhlovodíků agonisté   genetika   metabolismus   MeSH
• senioři MeSH
• transfekce MeSH
• transkripční faktory bHLH agonisté   genetika   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 1,10-phenanthroline MeSH Prohlížeč
• AHR protein, human MeSH Prohlížeč
• copper(II) nitrate MeSH Prohlížeč
• CYP1A1 protein, human MeSH Prohlížeč
• CYP1A2 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP1A1 MeSH
• cytochrom P-450 CYP1A2 MeSH
• dusičnany MeSH
• fenantroliny MeSH
• ligandy MeSH
• měď MeSH
• messenger RNA MeSH
• receptory aromatických uhlovodíků MeSH
• transkripční faktory bHLH MeSH

Azole antifungal ketoconazole (KET) was demonstrated to activate aryl hydrocarbon receptor (AhR). Since clinically used KET is a racemic mixture of two cis-enantiomers (2R,4S)-(+)-KET and (2S,4R)-(-)-KET, we examined the effects of KET enantiomers on AhR signaling pathway. (+)-KET dose-dependently activated AhR in human gene reporter cell line AZ-AHR, and displayed 5-20× higher agonist activity (efficacy), as compared to (-)-KET; both enantiomers were AhR antagonists with equal potency (IC50). Consistently, (+)-KET strongly induced CYP1A1 mRNA and protein in human HepG2 cells, while (-)-KET exerted less than 10% of (+)-KET activity. In primary human hepatocytes, both enantiomers preferentially induced CYP1A2 over CYP1A1 mRNA and protein, and the potency of (+)-KET was slightly higher as compared to (-)-KET. Ligand binding assay with guinea pig liver cytosols revealed that both (+)-KET and (-)-KET are weak ligands of AhR that displaced [3H]-TCDD with comparable potency. Similarly, both enantiomers weakly transformed AhR to DNA-binding form with similar potency, as showed by EMSA, in guinea pig liver cytosolic extracts and nuclear extracts from mouse Hepa-1 cells. We also examined effects of KET on glucocorticoid receptor (GR), a regulator of AhR activity. Both KET enantiomers antagonized GR with similar potency, as revealed by gene reporter assay in AZ-GR cell line and down-regulation of tyrosine aminotransferase mRNA in human hepatocytes. Finally, we demonstrate enantiospecific antifungal activities of KET enantiomers in six Candida spp. strains. In conclusion, the significance of current study is providing the first evidence of enatiospecific effects of cis-enantiomers of ketoconazole on AhR-CYP1A pathway.

• MeSH
• antifungální látky chemie   farmakologie   MeSH
• buňky Hep G2 MeSH
• Candida účinky léků   MeSH
• cytochrom P-450 CYP1A1 genetika   metabolismus   MeSH
• cytochrom P-450 CYP1A2 genetika   metabolismus   MeSH
• genetická transkripce účinky léků   MeSH
• hepatocyty účinky léků   metabolismus   MeSH
• ketokonazol chemie   farmakologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• morčata MeSH
• myši MeSH
• receptory aromatických uhlovodíků metabolismus   MeSH
• senioři MeSH
• signální transdukce účinky léků   MeSH
• stereoizomerie MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• morčata MeSH
• mužské pohlaví MeSH
• myši MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• antifungální látky MeSH
• cytochrom P-450 CYP1A1 MeSH
• cytochrom P-450 CYP1A2 MeSH
• ketokonazol MeSH
• messenger RNA MeSH
• receptory aromatických uhlovodíků MeSH

The protoberberine alkaloid palmatine is present in preparations from medicinal plants such as Coptis chinensis and Corydalis yanhusuo. This study examined whether palmatine affects the expression of cytochromes P450 (CYPs) 1A1 and 1A2 in primary cultures of human hepatocytes and human hepatoma HepG2 cells grown as monolayer or spheroids. Gene reporter assays showed that palmatine significantly activated the aryl hydrocarbon receptor (AhR) and increased the activity of CYP1A1 gene promoter in transiently transfected HepG2 cells. In HepG2 monolayer culture, palmatine also significantly increased mRNA and activity levels of CYP1A1, albeit with considerably less potency than 2,3,7,8-tetrachlorodibenzo-p-dioxin, a prototypical CYP1A inducer. On the other hand, CYP1A activity was not significantly elevated by palmatine in HepG2 spheroids. Moreover, palmatine induced mild or negligible changes in CYP1A1 and CYP1A2 mRNA expression without affecting CYP1A activity levels in primary human hepatocytes. It is concluded that palmatine activates the AhR-CYP1A pathway in HepG2 monolayer, while the potential for CYP1A induction is irrelevant in cell systems which are closer to the in vivo situation, i.e. in HepG2 spheroids and primary cultures of human hepatocytes. Possible induction of CYP1A enzymes by palmatine in vivo remains to be investigated.

• Klíčová slova
• Alkaloid, Aryl hydrocarbon receptor, CYP1A1, Cytochrome P450, Herb–drug interactions, Palmatine,
• MeSH
• berberin chemie   farmakologie   MeSH
• berberinové alkaloidy chemie   farmakologie   MeSH
• buňky Hep G2 MeSH
• cytochrom P-450 CYP1A1 genetika   metabolismus   MeSH
• cytochrom P-450 CYP1A2 genetika   metabolismus   MeSH
• hepatocyty účinky léků   MeSH
• lidé MeSH
• molekulární struktura MeSH
• receptory aromatických uhlovodíků genetika   metabolismus   MeSH
• regulace genové exprese účinky léků   MeSH
• transkripční faktory bHLH genetika   metabolismus   MeSH
• viabilita buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• AHR protein, human MeSH Prohlížeč
• berberin MeSH
• berberinové alkaloidy MeSH
• CYP1A1 protein, human MeSH Prohlížeč
• CYP1A2 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP1A1 MeSH
• cytochrom P-450 CYP1A2 MeSH
• palmatine MeSH Prohlížeč
• receptory aromatických uhlovodíků MeSH
• transkripční faktory bHLH MeSH

UNLABELLED: 1. Aristolochic acid I (AAI) is the predominant component in plant extract of Aristolochia genus that is involved in development of aristolochic acid nephropathy, Balkan endemic nephropathy and urothelial cancer. The diseases do not develop in all individuals exposed to AAI and patients exhibit different clinical outcomes. Differences in the activities of enzymes catalyzing the metabolism of AAI might be one of the reasons for this individual susceptibility. 2. Understanding which human enzymes are involved in reductive activation of AAI generating AAI-DNA adducts, and/or its detoxication to the O-demethylated metabolite, aristolochic acid Ia (AAIa), is necessary in the assessment of the susceptibility to this compound. 3. This review summarizes the results of the latest studies utilizing genetically engineered mouse models to identify which human and rodent enzymes catalyze the reductive activation of AAI to AAI-DNA adducts and its oxidative detoxication to AAIa in vivo. 4. The use of hepatic cytochrome P450 (Cyp) reductase null (HRN) mice, in which NADPH:Cyp oxidoreductase (Por) is deleted in hepatocytes, Cyp1a1((-/-)), Cyp1a2((-/-)) single-knockout, Cyp1a1/1a2((-/-)) double-knockout and CYP1A-humanized mice revealed that mouse and human CYP1A1 and 1A2, besides mouse NAD(P)H: quinone oxidoreductase, were involved in the activation of AAI but CYP1A1 and 1A2 also oxidatively detoxified AAI.

• MeSH
• adukty DNA metabolismus   MeSH
• cytochrom P-450 CYP1A1 genetika   metabolismus   MeSH
• cytochrom P-450 CYP1A2 genetika   metabolismus   MeSH
• enzymy genetika   metabolismus   MeSH
• inhibitory enzymů farmakologie   MeSH
• karcinogeny metabolismus   farmakokinetika   MeSH
• kyseliny aristolochové metabolismus   farmakokinetika   toxicita   MeSH
• lidé MeSH
• metabolická inaktivace * MeSH
• myši knockoutované * MeSH
• myši MeSH
• NAD(P)H dehydrogenasa (chinon) antagonisté a inhibitory   MeSH
• NADPH-cytochrom c-reduktasa genetika   metabolismus   MeSH
• nemoci ledvin chemicky indukované   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• adukty DNA MeSH
• aristolochic acid I MeSH Prohlížeč
• CYP1A1 protein, human MeSH Prohlížeč
• CYP1A2 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP1A1 MeSH
• cytochrom P-450 CYP1A2 MeSH
• enzymy MeSH
• inhibitory enzymů MeSH
• karcinogeny MeSH
• kyseliny aristolochové MeSH
• NAD(P)H dehydrogenasa (chinon) MeSH
• NADPH-cytochrom c-reduktasa MeSH
• NQO1 protein, human MeSH Prohlížeč