Cytochrome P450 2A13 is an omitted brother of CYP2A6 that has an important role in the drug metabolism of liver. Due to extrahepatic expression, it has gained less attention than CYP2A6, despite the fact that it plays a significant role in toxicant-induced pulmonary lesions and, therefore, lung cancer. The purpose of this mini-review is to summarize the basic knowledge about this enzyme in relation to the substrates, inhibitors, genetic polymorphisms, and transcriptional regulation that are known so far (September 2021).

• MeSH
• aromatické hydroxylasy antagonisté a inhibitory   genetika   metabolismus   MeSH
• lidé MeSH
• methoxsalen farmakologie   MeSH
• nádory plic enzymologie   genetika   patologie   MeSH
• plíce enzymologie   metabolismus   patologie   MeSH
• polymorfismus genetický * MeSH
• regulace genové exprese enzymů * MeSH
• regulace genové exprese u nádorů * MeSH
• substrátová specifita MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Aryl hydrocarbon receptor (AhR) is a transcription factor, the activity of which is modulated by hormones including glucocorticoids and estrogens. In this study, we examined the effects of triiodothyronine (T3), a ligand and activator of thyroid hormone receptor (TR), on transcriptional activity of AhR and the expression of its target gene CYP1A1. Study was carried out in human hepatocellular carcinoma cells HepG2 and primary cultures of human hepatocytes (HH). Gene reporter assay in stably transfected AZ-AhR cells revealed that T3 dose-dependently augmented 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible AhR-dependent luciferase activity. In contrast, T3 had no effect on TCDD-inducible expression of CYP1A1 mRNA, protein and catalytic activity. Incubation of human hepatocytes with T3 had modulatory and inter-individual (7 cell cultures from 7 different liver donors) effects on both basal and dioxin-inducible CYP1A1/2. Since there was no correlation between T3 effects on CYP1A expression and T3-dependent expression of Spot14 mRNA, the involvement of additional factors besides TR is supposed. Overall, the co-incubation of normal and cancer human hepatic cells with TCDD and T3 suggested transcriptional cross-talk between AhR and TR, which may have physiological and toxicological implications.

• MeSH
• buňky Hep G2 MeSH
• cytochrom P-450 CYP1A1 biosyntéza   genetika   MeSH
• dospělí MeSH
• hepatocyty účinky léků   metabolismus   MeSH
• induktory cytochromu P450 CYP1A2 toxicita   MeSH
• interakce mezi receptory a ligandy MeSH
• kokultivační techniky MeSH
• lidé středního věku MeSH
• lidé MeSH
• polychlorované dibenzodioxiny toxicita   MeSH
• receptory aromatických uhlovodíků genetika   metabolismus   MeSH
• receptory thyreoidních hormonů metabolismus   MeSH
• senioři MeSH
• trijodthyronin farmakologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

In the recent years, a therapeutic potential of disulfiram (Antabuse) complex with copper, as an anticancer drug, was recognized towards several cancer cell lines. The proteasome was suggested as one of the cellular targets for this compound. As the therapeutic use of diethyldithiocarbamate-copper complex (CuET) is expected to increase, it is of great interest to know whether this compound may be the source of drug-drug interactions via the induction of biotransformation enzymes, especially cytochromes P450 (CYPs). To this purpose, we examined the effect of CuET and compared it with typical inducers (rifampicin and dioxin) of CYPs and with well-established proteasome inhibitors (MG132 and bortezomib). Diethyldithiocarbamate-copper complex revealed inconsistent and rather modulatory effect on the expression of CYP1A2 and CYP3A4 in several cultures of human hepatocytes. Moreover, it was able to cause neither ubiquitin accumulation nor significant and dose-dependent inhibition of proteasome activity. It had no effect on essential transcription factors involved in regulation of selected CYPs, aryl hydrocarbon (AhR) nor pregnane X receptor (PXR). However, the AhR protein was increased in majority of examined hepatocyte cultures. The main finding of this study is that: (i) disulfiram-copper complex is not the cause of drug-drug interactions via CYP1A2/3A4 induction; (ii) proteasome inhibitors may have different impact on studied parameters in given in vitro system.

• MeSH
• cytochrom P-450 CYP1A2 metabolismus   MeSH
• cytochrom P-450 CYP3A metabolismus   MeSH
• dithiokarb farmakologie   MeSH
• dospělí MeSH
• hepatocyty účinky léků   metabolismus   MeSH
• inhibitory proteasomu farmakologie   MeSH
• kultivované buňky MeSH
• lékové interakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• měď farmakologie   MeSH
• proteasomový endopeptidasový komplex metabolismus   MeSH
• senioři MeSH
• steroidní receptory metabolismus   MeSH
• transkripční faktory metabolismus   MeSH
• uhlovodíky metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: We carried out a test whether or not transplant drugs such as cyclosporine A, Rapamycin (Sirolimus), Tacrolimus, Everolimus and Mycophenolate mofetil affects the expression of phase II enzymes comprising of UDP-glucuronosyltransferases (UGTs) and glutathione-S-transferases (GSTs), and antioxidant enzymes that consist of glutathione reductase (GSR), glutathione peroxidase 1 (GPX1) and heme-oxygenase 1 (HMOX1). METHODS: Experiments were performed in primary cultures of human hepatocytes and in human hepatocarcinoma HepG2 cells, the models of metabolically competent and incompetent cells, respectively. We used quantitative real-time PCR. RESULTS: We found that none of the tested compounds affected the expression of investigated genes in human hepatocytes. On the other hand, Mycophenolate mofetil induced GPX1 mRNA, although it suppressed mRNA level of UGT1A4/1A9/2B7/2B10, GSTA1/O1/T1, GSR and HMOX1 in HepG2 cells. CONCLUSION: We showed that the tested transplant drugs have no effect on the expression of selected phase II and antioxidant enzymes in human hepatocytes. Nevertheless, the experiments carried out in two common and frequently used in vitro cellular models, we emphasize that finding based solely on carcinoma cells must be taken with caution when transposing to in vivo situations.

• MeSH
• antioxidancia metabolismus   MeSH
• buňky Hep G2 MeSH
• glukuronosyltransferasa metabolismus   MeSH
• glutathionperoxidasa metabolismus   MeSH
• glutathionreduktasa metabolismus   MeSH
• glutathiontransferasa metabolismus   MeSH
• hemoxygenasa-1 metabolismus   MeSH
• hepatocelulární karcinom metabolismus   MeSH
• hepatocyty účinky léků   metabolismus   MeSH
• imunosupresiva farmakologie   MeSH
• lidé MeSH
• messenger RNA metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádory jater metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

P-glycoprotein (P-gp) inhibition represents a promising therapeutic strategy for oncologic patients. The inhibition by naturally occurring anthocyans would bring certain benefits. Unfortunately, due to the low bioavailability and consequently low blood level, they cannot be used for cancer therapy. However, due to the food supplementation, significant concentration can raise up in the intestine, where P-gp is abundantly expressed. As many drugs are orally taken, simultaneous administration might affect the concentration of these drugs in the blood. Here, we found that anthocyanidins (aglycons) but not anthocyanins (glycosides) can significantly inhibit P-gp up to 60% of positive control, verapamil. This inhibitory activity was observed for 500 μm concentrations of malvidin and pelargonidin. We conclude that these compounds may be the source of food-drug interactions either for orally taken drugs or for intravenously administered drugs eliminated via biliary excretion which are the substrates of P-gp.

• MeSH
• anthokyaniny aplikace a dávkování   metabolismus   MeSH
• aplikace orální MeSH
• fluoresceiny aplikace a dávkování   metabolismus   MeSH
• interakce mezi potravou a léky * fyziologie   MeSH
• lidé MeSH
• P-glykoprotein antagonisté a inhibitory   metabolismus   MeSH
• potravní doplňky * MeSH
• prasata MeSH
• verapamil aplikace a dávkování   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Environmental pollutants parathion, bisphenol A and paraquat were not systematically studied towards the effects on the expression of phase I xenobiotics-metabolizing cytochromes P450 (CYPs). We monitored their effects on the expression of selected CYPs in primary cultures of human hepatocytes. Moreover, we investigated their effects on the receptors regulating these CYPs, particularly arylhydrocarbon receptor (AhR), pregnane X receptor (PXR) and glucocorticoid receptor (GR) by gene reporter assays. We found that parathion and bisphenol A are the activators of AhR. Moreover, they are the inducers of CYP1A1 mRNA in hepatoma cells HepG2 as well as in human hepatocytes by AhR-dependent mechanism via formation of AhR-DNA-binding complex, as revealed by gel shift assay. All three compounds possessed anti-glucocorticoid action as revealed by GR-dependent gene reporter assay and a decline in tyrosine aminotransferase (TAT) gene expression in human hepatocytes. Moreover, parathion and bisphenol A are the activators of PXR and inducers of CYP3A4 mRNA and protein in the primary cultures of human hepatocytes. In conclusion, the studied compounds displayed distinct activities towards nuclear receptors involved in many biological processes and these findings may help us to better understand their adverse actions in pathological states followed after their exposure.

• MeSH
• aktivace transkripce účinky léků   MeSH
• benzhydrylové sloučeniny metabolismus   toxicita   MeSH
• buňky Hep G2 MeSH
• enzymová indukce MeSH
• fenoly metabolismus   toxicita   MeSH
• hepatocyty účinky léků   enzymologie   MeSH
• I. fáze biotransformace MeSH
• kultivované buňky MeSH
• látky znečišťující životní prostředí metabolismus   toxicita   MeSH
• lidé středního věku MeSH
• lidé MeSH
• paraquat metabolismus   toxicita   MeSH
• parathion metabolismus   toxicita   MeSH
• primární buněčná kultura MeSH
• receptory aromatických uhlovodíků genetika   metabolismus   MeSH
• receptory glukokortikoidů genetika   metabolismus   MeSH
• regulace genové exprese enzymů účinky léků   MeSH
• reportérové geny MeSH
• steroidní receptory genetika   metabolismus   MeSH
• systém (enzymů) cytochromů P-450 biosyntéza   genetika   MeSH
• viabilita buněk účinky léků   MeSH
• xenobiotika metabolismus   toxicita   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

In this paper we investigated the effects of several drugs used in transplant medicine, i.e. cyclosporine A, tacrolimus, rapamycin, everolimus, mycophenolate mofetil, fluvastatin and rosuvastatin, on the expression of major drug-metabolizing enzymes in human hepatocytes. Moreover, we tested the ability of these drugs to affect transcriptional activity of glucocorticoid (GR) and aryl hydrocarbon receptor (AhR). We found that most of tested compounds did not induce expression of CYP1A1/1A2/3A4/2A6/2B6/2C9 mRNAs in human hepatocytes. Slight induction was observed for CYP2A6/2C9 mRNAs and CYP2A6 protein in the rapamycin-treated hepatocytes. Decrease of CYP2A6 and CYP2B6 proteins was observed in rosuvastatin-treated cells. Mycophenolate mofetil antagonized the effects of dexamethasone on GR but it potentiated the action of dioxin on AhR. Induction of CYP1A1 mRNA in HepG2 cells by dioxin was modestly antagonized by mycophenolate mofetil, while the induction by benzo[a]pyren or S-omeprazole was significantly potentiated by this drug. In general, tested compounds can be considered safe in the terms of possible drug-drug interaction caused by induction of drug-metabolizing cytochromes P450. Nevertheless, mycophenolate mofetil is of possible concern and its combination with drugs, environmental pollutants or food constituents, which activate AhR, may represent a significant toxicological risk.

• MeSH
• buněčné linie MeSH
• buňky Hep G2 MeSH
• dexamethason farmakologie   MeSH
• dospělí MeSH
• hepatocyty účinky léků   metabolismus   MeSH
• imunologické faktory farmakologie   MeSH
• kultivované buňky MeSH
• lékové interakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• luciferasy genetika   metabolismus   MeSH
• messenger RNA metabolismus   MeSH
• polychlorované dibenzodioxiny farmakologie   MeSH
• receptory aromatických uhlovodíků genetika   MeSH
• receptory glukokortikoidů genetika   MeSH
• systém (enzymů) cytochromů P-450 genetika   MeSH
• xenobiotika metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Sibutramine is a serotonin-norepinephrine reuptake inhibitor that was used for weight-loss management in obese patients. Even though it was officially withdrawn from the market in 2010, it is still present in some tainted weight-loss pills (as reported by US Food and Drug Administration). Thus, it is still reasonable to study the effects of this compound. The aim of this work was to investigate the potential of sibutramine to induce CYP1A1/CY3A4 in human cancer cell lines and CYP1A1/2, CYP2A6, CYP2B6, and CYP3A4 in human hepatocytes, a competent model of metabolically active cells. The levels of mRNA and protein of CYP1A1/1A2/3A4/2A6/2B6 were compared with the typical inducers, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and rifampicin (RIF) for CYP1A1/2 and for other CYPs, respectively. The mRNA and protein levels of all genes in either cancer cell lines or human hepatocytes were induced when treated with typical inducers but not with sibutramine.

• MeSH
• cyklobutany farmakologie   MeSH
• hepatocyty účinky léků   enzymologie   MeSH
• izoenzymy biosyntéza   MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• látky proti obezitě farmakologie   MeSH
• lidé MeSH
• messenger RNA genetika   izolace a purifikace   MeSH
• nádorové buněčné linie MeSH
• primární buněčná kultura MeSH
• systém (enzymů) cytochromů P-450 biosyntéza   MeSH
• western blotting MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Khellin and visnagin are two furanochromones that can be frequently found in ethnomedical formulations in Asia and the Middle East. Both compounds possess anti-inflammatory and analgesic properties, therefore modern medicine uses these compounds or structurally related derivatives for treatment of vitiligo, bronchial asthma and renal colics. Despite their frequent usage, the potential toxic properties of visnagin and khellin are not well characterized up-to-now. Many natural compounds modulate the expression and activity of cytochrome P450 1A1 (CYP1A1), which is well-known to bioactivate pro-carcinogens. The expression of this enzyme is controlled by the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor and regulator of drug metabolism. Here, we investigated the influence of both furanochromones on AHR signaling in human HepG2 hepatocarcinoma cells and primary human hepatocytes. Both compounds transactivated xenobiotic response element (XRE)-driven reporter gene activity in a dose-dependent manner and induced CYP1A1 transcription in HepG2 cells and primary hepatocytes. The latter was abolished in presence of a specific AHR antagonist. CYP1A enzyme activity assays done in HepG2 cells and primary hepatocytes revealed an inhibition of enzyme activity by both furanochromones, which may become relevant regarding the metabolism of xenobiotics and co-administered therapeutic drugs. The observed induction of several other members of the AHR gene battery, whose gene products are involved in regulation of cell growth, differentiation and migration, indicates that a further toxicological characterization of visnagin and khelllin is urgently required in order to minimize potential drug-drug interactions and other toxic side-effects that may occur during therapeutic usage of these furanochromones.

• MeSH
• aktivace enzymů účinky léků   MeSH
• aromatické hydroxylasy metabolismus   MeSH
• buněčné linie MeSH
• cytochrom P-450 CYP1A1 genetika   metabolismus   MeSH
• exprese genu MeSH
• hepatocyty účinky léků   metabolismus   MeSH
• khelin farmakologie   MeSH
• lidé MeSH
• receptory aromatických uhlovodíků metabolismus   MeSH
• regulace genové exprese účinky léků   MeSH
• reportérové geny MeSH
• signální transdukce účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Valproic acid (VPA) is a wide spread anticonvulsant and mood-stabilizing agent, the use of which is associated with hepatotoxicity, bone marrow suppression and osteomalacia. In the current paper we propose a possible mechanism of VPA-induced osteomalacia involving accelerated catabolism of 1α,25(OH)(2)-vitamin D3 (VD3) due to increased expression of CYP24. We demonstrate that VPA strongly potentiates CYP24 mRNA expression by VD3 in human hepatocytes (HH) and in human embryonic kidney cells (HEK293). By the method of gene reporter assay we found that VPA increases basal and VD3-inducible activity of CYP24 promoter (pCYP24-luc) in human liver adenocarcinoma (HepG2) and in HEK293 cells in dose-dependent manner. In order to delineate the role of inhibitory effects of VPA on histone deacetylase 1 (HDAC1), we compared the effects of VPA with trichostatin A (TSA) on basal and inducible levels of CYP24 mRNA and pCYP24-luc transactivation. Transactivation of CYP24 promoter by VD3 was enhanced in the presence of both TSA and VPA. In contrast, VD3-inducible expression of CYP24 mRNA was enhanced by VPA but not by TSA, implying that HDAC1 inhibition is not the major reason for VPA effects on CYP24. We examined the effects of VPA on mitogen-activated protein kinases as the important transcriptional regulators of VDR. VPA activated extracellular signal-regulated kinase (ERK) but not c-Jun-N-terminal kinase (JNK) and p38 MAPKs. In conclusion, VPA enhances transcriptional activity of VDR and increases expression of CYP24 mRNA in the presence of VD3 in physiological concentrations. The mechanism involves activation of ERK and partly the inhibition of HDAC1.

• MeSH
• antikonvulziva toxicita   MeSH
• cholekalciferol farmakologie   MeSH
• extracelulárním signálem regulované MAP kinasy genetika   metabolismus   MeSH
• HEK293 buňky MeSH
• hepatocyty účinky léků   MeSH
• histondeacetylasa 1 biosyntéza   genetika   MeSH
• kyselina valproová toxicita   MeSH
• lidé MeSH
• luciferasy genetika   MeSH
• messenger RNA biosyntéza   genetika   MeSH
• osteomalacie chemicky indukované   patologie   MeSH
• plazmidy genetika   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• receptory kalcitriolu účinky léků   MeSH
• steroidhydroxylasy biosyntéza   genetika   MeSH
• steroidní receptory účinky léků   MeSH
• transfekce MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• western blotting MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH