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1.
Physiol Rep ; 9(6): e14795, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33769703

RESUMO

Cytochrome P450 2E1 (CYP2E1)-associated reactive oxygen species production plays an important role in the development and progression of inflammatory liver diseases such as alcoholic steatohepatitis. We developed two new inhibitors for this isoenzyme, namely 12-imidazolyl-1-dodecanol (I-ol) and 1-imidazolyldodecane (I-an), and aimed to test their effects on non-alcoholic steatohepatitis (NASH). The fat-rich and CYP2E1 inducing Lieber-DeCarli diet was administered over 16 weeks of the experimental period to induce the disease in a rat model, and the experimental substances were administered simultaneously over the last four weeks. The high-fat diet (HFD) pathologically altered the balance of reactive oxygen species and raised the activities of the liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP) and γ-glutamyl-transferase (γ-GT); lowered the level of adiponectine and raised the one of tumor necrosis factor (TNF)-α; increased the hepatic triglyceride and phospholipid content and diminished the serum HDL cholesterol concentration. Together with the histological findings, we concluded that the diet led to the development of NASH. I-ol and, to a lesser extent, I-an shifted the pathological values toward the normal range, despite the continued administration of the noxious agent (HFD). The hepatoprotective drug ursodeoxycholic acid (UDCA), which is used off-label in clinical practice, showed a lower effectiveness overall. I-ol, in particular, showed extremely good tolerability during the acute toxicity study in rats. Therefore, cytochrome P450 2E1 may be considered a suitable drug target, with I-ol and I-an being promising drug candidates for the treatment of NASH.


Assuntos
Inibidores do Citocromo P-450 CYP2E1/administração & dosagem , Imidazóis/administração & dosagem , Imidazóis/química , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Inibidores do Citocromo P-450 CYP2E1/toxicidade , Modelos Animais de Doenças , Feminino , Imidazóis/toxicidade , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
2.
Can J Gastroenterol Hepatol ; 2021: 8854432, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33604316

RESUMO

Cytochrome P450 2E1 (CYP2E1) is a key target protein in the development of alcoholic and nonalcoholic fatty liver disease (FLD). The pathophysiological correlate is the massive production of reactive oxygen species. The role of CYP2E1 in the development of hepatocellular carcinoma (HCC), the final complication of FLD, remains controversial. Specifically, CYP2E1 has not yet been defined as a molecular target for HCC therapy. In addition, a CYP2E1-specific drug has not been developed. We have already shown that our newly developed CYP2E1 inhibitor 12-imidazolyl-1-dodecanol (I-ol) was therapeutically effective against alcoholic and nonalcoholic steatohepatitis. In this study, we investigated the effect of I-ol on HCC tumorigenesis and whether I-ol could serve as a possible treatment option for terminal-stage FLD. I-ol exerted a very highly significant antitumour effect against hepatocellular HepG2 cells. Cell viability was reduced in a dose-dependent manner, with only the highest doses causing a cytotoxic effect associated with caspase 3/7 activation. Comparable results were obtained for the model colorectal adenocarcinoma cell line, DLD-1, whose tumorigenesis is also associated with CYP2E1. Transcriptome analyses showed a clear effect of I-ol on apoptosis and cell-cycle regulation, with the increased expression of p27Kip1 being particularly noticeable. These observations were confirmed at the protein level for HepG2 and DLD-1 cells grafted on a chorioallantoic membrane. Cell-cycle analysis showed a complete loss of proliferating cells with a simultaneous increase in S-phase arrest beginning at a threshold dose of 30 µM. I-ol also reduced xenograft tumour growth in nude mice. This antitumour effect was not associated with tumour cachexia. I-ol was not toxic to healthy tissues or organs. This study demonstrates for the first time the therapeutic effect of the specific CYP2E1 inhibitor I-ol on the tumorigenesis of HCC. Our findings imply that I-ol can potentially be applied therapeutically on patients at the final stage of FLD.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Citocromo P-450 CYP2E1/metabolismo , Dodecanol , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Camundongos Nus , Estresse Oxidativo
3.
PLoS One ; 15(7): e0235990, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32701948

RESUMO

BACKGROUND AND AIMS: Alcoholic steatohepatitis (ASH)-the inflammation of fatty liver-is caused by chronic alcohol consumption and represents one of the leading chronic liver diseases in Western Countries. ASH can lead to organ dysfunction or progress to hepatocellular carcinoma (HCC). Long-term alcohol abstinence reduces this probability and is the prerequisite for liver transplantation-the only effective therapy option at present. Elevated enzymatic activity of cytochrome P450 2E1 (CYP2E1) is known to be critically responsible for the development of ASH due to excessively high levels of reactive oxygen species (ROS) during metabolization of ethanol. Up to now, no rational drug discovery process was successfully initiated to target CYP2E1 for the treatment of ASH. METHODS: In this study, we applied a rational drug design concept to develop drug candidates (NCE) including preclinical studies. RESULTS: A new class of drug candidates was generated successfully. Two of the most promising small compounds named 12-Imidazolyl-1-dodecanol (abbr.: I-ol) and 1-Imidazolyldodecane (abbr.: I-an) were selected at the end of this process of drug discovery and developability. These new ω-imidazolyl-alkyl derivatives act as strong chimeric CYP2E1 inhibitors at a nanomolar range. They restore redox balance, reduce inflammation process as well as the fat content in the liver and rescue the physiological liver architecture of rats consuming continuously a high amount of alcohol. CONCLUSIONS: Due to its oral application and therapeutic superiority over an off-label use of the hepatoprotector ursodeoxycholic acid (UDCA), this new class of inhibitors marks the first rational, pharmaceutical concept in long-term treatment of ASH.


Assuntos
Inibidores do Citocromo P-450 CYP2E1/uso terapêutico , Citocromo P-450 CYP2E1/metabolismo , Fígado Gorduroso Alcoólico/tratamento farmacológico , Alcanos/síntese química , Alcanos/farmacologia , Alcanos/uso terapêutico , Animais , Citocromo P-450 CYP2E1/química , Inibidores do Citocromo P-450 CYP2E1/síntese química , Inibidores do Citocromo P-450 CYP2E1/farmacologia , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/patologia , Feminino , Células Hep G2 , Humanos , Lipoproteínas VLDL/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Índice de Gravidade de Doença , Triglicerídeos/sangue , Ácido Ursodesoxicólico/análise
4.
Z Naturforsch C J Biosci ; 59(7-8): 599-605, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15813386

RESUMO

The inhibitory potency of four alkylphospholipids: rac-1-O-phosphocholine-2-hydroxy-octadecane (rac-2-OH), rac-1-O-phosphocholine-2-O-acetyl-octadecane (rac-2-O-acetyl), rac-1-O-phosphocholine-2-amino-octadecane (rac-2-NH2) and rac-1-O-phosphocholine-2-N-acetyloctadecane (rac-2-N-acetyl), on the cytochrome P450-dependent monooxygenase activity has been evaluated. The IC50 values of the alkylphosphocholines with 7-ethoxycoumarin as substrate in liver microsomal fractions of PB-treated rats and with a reconstituted CYP2B1: NADPH-P450-reductase system are in the range of 3.2-5.0 microM and 2.8-3.5 microM, respectively. Lineweaver-Burk plots with the inhibitors in concentrations that were found to cause roughly a 50% inhibition and with 7-ethoxycoumarin as substrate revealed for all four alkylphospholipids a competitive inhibition type. The degree of the competitive inhibition is quantified by the Ki values. With liver microsomal fractions of PB-treated rats, the Ki values of rac-2-OH (Ki = 1.36 microM) and rac-2-O-acetyl (Ki = 1.33 microM) differs slightly from those of rac-2-NH2 (Ki = 2.2 microM) and rac-2-N-acetyl (Ki = 2.2 microM), but with the reconstituted CYP2B1: NADPH-P450-reductase system all Ki values are in the small range of 1.8 - 2.6 microM, indicating that the short substituted group at the 2-position (OH; O-acetyl; NH2; N-acetyl) of the long chain octadecanol part of the phosphodiesters exhibit no essential role on the strong inhibitory potency of these alkylphosphocholines on the 7-ethoxycoumarin-O-deethylase activity.


Assuntos
Citocromo P-450 CYP2B1/antagonistas & inibidores , Inibidores das Enzimas do Citocromo P-450 , Microssomos Hepáticos/enzimologia , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Animais , Inibidores Enzimáticos/farmacologia , Cinética , Masculino , Ratos , Ratos Sprague-Dawley
5.
Arzneimittelforschung ; 54(1): 78-83, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-14979613

RESUMO

Catalytic activities of native human CYP3A4-mediated reactions as well as drug interactions were directly evaluated by isolated reconstituted human CYP3A4: NADPH-cytochrome P450 reductase systems. The SDS-PAGE pure CYP3A4 and human NADPH-cytochrome P450 reductase had been incorporated into a binary vesicular phospholipid system of dilauroyl-phosphatidyl-choline and phosphatidyl-serine which had proven to achieve optimal nifedipine oxidase activity (19.6 nmol nifedipine oxidized x min(-1) x nmol CYP3A4(-1)). The IC50 values of ketoconazole (CAS 65 277-42-1) (approximately 3 micromol/l), quinidine (CAS 56-54-2) (approximately 5 micromol/l), mifepristone (CAS 84 371-65-3) (-8 micromol/l), 17alpha-ethinylestradiol (CAS 57-63-6) (approximately 17 micromol/l), cimetidine (CAS 51 481-61-9) (approximately 46 micromol/l), FK 506 (tacrolimus) (CAS 104 987-11-3) (approximately 53 micromol/l), naringenin (CAS 480-41-1) (approximately 87 micromol/l), and cyclosporine A (CAS 59 865-13-3) (approximately 90 micromol/l) indicate that all these drugs have an inhibitory effect on nifedipine (CAS 21 829-25-4) metabolism, whereas the drug quinine (CAS 130-95-0) did not elicit any significant inhibition.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Interações Medicamentosas , NADPH-Ferri-Hemoproteína Redutase/metabolismo , Antifúngicos/farmacologia , Antimaláricos/farmacologia , Catálise , Cromatografia Líquida de Alta Pressão , Cimetidina/farmacologia , Ciclosporina/farmacologia , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/química , Eletroforese em Gel de Poliacrilamida , Antagonistas de Estrogênios/farmacologia , Etinilestradiol/farmacologia , Flavanonas/farmacologia , Antagonistas de Hormônios/farmacologia , Humanos , Imunossupressores/farmacologia , Técnicas In Vitro , Cetoconazol/farmacologia , Microssomos Hepáticos/enzimologia , Mifepristona/farmacologia , Fosfolipídeos/química , Quinidina/farmacologia , Quinina/farmacologia , Tacrolimo/farmacologia
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