RESUMO
Interleukin-8 (IL-8) plays a central role in the pathogenesis of Helicobacter pylori infection. We used four different H. pylori strains isolated from patients with gastritis or duodenal ulcer disease to examine their differential effects on signaling pathways and IL-8 gene response in gastric epithelial cells. IL-8 mRNA level is elevated in response to high (100) multiplicity of infection (MOI) independent of cagA, vacA, and dupA gene characteristics. By lower MOIs (1 or 10), only cagA ( + ) strains significantly induce IL-8 gene expression. This is based on differential regulation of IL-8 promoter activity. Analysis of intracellular signaling pathways indicates that H. pylori clinical isolates induce IL-8 gene transcription through NF-κB p65, but by a MOI-dependent differential activation of MAPK pathways. Thus, the major virulence factors of H. pylori CagA, VacA, and DupA might play a minor role in the level of IL-8 gene response to a high bacterial load.
Assuntos
Carga Bacteriana , Regulação da Expressão Gênica , Helicobacter pylori/patogenicidade , Interleucina-8/metabolismo , Transdução de Sinais , Fatores de Virulência/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Linhagem Celular , Úlcera Duodenal/imunologia , Úlcera Duodenal/microbiologia , Úlcera Duodenal/fisiopatologia , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Gastrite/imunologia , Gastrite/microbiologia , Gastrite/fisiopatologia , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/classificação , Helicobacter pylori/genética , Helicobacter pylori/isolamento & purificação , Humanos , Interleucina-8/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Regiões Promotoras Genéticas/genética , Estômago/citologia , Estômago/imunologia , Estômago/microbiologia , Transcrição Gênica , Fatores de Virulência/genéticaRESUMO
Induction of apoptosis by the PP1/PP2A inhibitor calyculin A was inhibited if the CaMKII inhibitor KN-93 was added no later than 10 min after addition of calyculin A. The physiological relevance and mechanism of CaMKII during apoptosis, however, remains largely unclear. Here we show in MDCK and gastric parietal cells that normal transregulation of CaMKII terminates the initial burst of autophosphorylation after only 10 min. The kinetics of CaMKII involved transregulation by PP1, PP2A, PP2B and PKCalpha. Transregulation of CaMKII resulted in two kinetic phases for phosphorylation of the autoactivation site at T286/287. During the initial phase, there was a clear peak of phosphorylation that lasted 10 min. This phase was subsequently followed by a half but constant level of T286/287 phosphorylation. Calyculin A perturbed this transregulation, resulting in a hyperphosphorylated CaMKII. This effect of CA on the kinetics of CaMKII was observed in vivo as well as in vitro using isolated tubulovesicles. Calyculin A-induced hyperphosphorylation of CaMKII appears to be at least one mechanism used by cells to trigger apoptosis. Therefore, stringent limitation of CaMKII autophosphorylation at T286/287 by transregulation and prevention of hyperphosphorylation seems to restrict apoptosis.
Assuntos
Apoptose , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Animais , Benzilaminas/farmacologia , Linhagem Celular , Forma Celular/efeitos dos fármacos , Cães , Inibidores Enzimáticos/farmacologia , Membranas Intracelulares/efeitos dos fármacos , Membranas Intracelulares/enzimologia , Cinética , Masculino , Toxinas Marinhas , Camundongos , Proteínas Mutantes/metabolismo , Oxazóis/farmacologia , Fosforilação/efeitos dos fármacos , Ratos , Ratos Wistar , Sulfonamidas/farmacologia , Fatores de TempoRESUMO
BACKGROUND & AIMS: K(+) recycling at the apical membrane of gastric parietal cells is a prerequisite for gastric acid secretion. Two K(+) channels are currently being considered for this function, namely KCNQ1 and inwardly rectifying K(+) channels (Kir). This study addresses the subcellular localization, trafficking, and potential functional significance of KCNQ1 and Kir4.1 channels during stimulated acid secretion. METHODS: The effect of pharmacologic KCNQ1 blockade on acid secretion was studied in cultured rat and rabbit parietal cells and in isolated mouse gastric mucosa. The subcellular localization of KCNQ1 and Kir4.1 was determined in highly purified membrane fractions by Western blot analysis as well as in fixed and living cells by confocal microscopy. RESULTS: In cultured parietal cells and in isolated gastric mucosa, a robust acid secretory response was seen after complete pharmacologic blockade of KCNQ1. Both biochemical and morphologic data demonstrate that Kir4.1 and KCNQ1 colocalize with the H(+)/K(+)-ATPase but do so in different tubulovesicular pools. All Kir4.1 translocates to the apical membrane after stimulation in contrast to only a fraction of KCNQ1, which mostly remains cytoplasmic. CONCLUSIONS: Acid secretion can be stimulated after complete pharmacologic blockade of KCNQ1 activity, suggesting that additional apical K(+) channels regulate gastric acid secretion. The close association of Kir4.1 channels with H(+)/K(+)-ATPase in the resting and stimulated membrane suggests a possible role for Kir4.1 channels during the acid secretory cycle.
Assuntos
Ácido Gástrico/metabolismo , Canal de Potássio KCNQ1/metabolismo , Células Parietais Gástricas/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Animais , Western Blotting , Células Cultivadas , Cromanos/farmacologia , Modelos Animais de Doenças , ATPase Trocadora de Hidrogênio-Potássio/metabolismo , Imuno-Histoquímica , Imunoprecipitação , Canal de Potássio KCNQ1/antagonistas & inibidores , Masculino , Camundongos , Microscopia Confocal , Células Parietais Gástricas/citologia , Células Parietais Gástricas/efeitos dos fármacos , Canais de Potássio Corretores do Fluxo de Internalização/antagonistas & inibidores , Coelhos , Ratos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/metabolismo , Sulfonamidas/farmacologiaRESUMO
The proximicins A-C (1-3) are novel naturally occurring gamma-peptides with a hitherto unknown 2,4-disubstituted furan amino acid as a core structure. They show a moderate cytotoxic activity and induce upregulation of cell cycle regulating proteins (p53 and p21) and lead to cell cycle arrest in G0/G1-phase. Hybrid molecules combining structural motifs of the proximicins and of netropsin (4), a structurally related natural product, seem to have similar effects. Herein we describe the synthesis of a netropsin-proximicin-hybrid library and its evaluation regarding cytotoxicity and minor groove binding activity.
Assuntos
Antineoplásicos/síntese química , DNA/metabolismo , Netropsina/análogos & derivados , Antineoplásicos/química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , DNA/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Netropsina/síntese química , Netropsina/toxicidade , Proteína Supressora de Tumor p53/metabolismoRESUMO
The new benzoxazole derivative nataxazole was isolated from Streptomyces sp. (strain Tü 6176). Nataxazole is related in structure to the potent antitumor compounds UK-1 and AJI9561 and showed similar strong growth inhibitory activity against various human tumor cell lines.
Assuntos
Antineoplásicos/farmacologia , Benzoxazóis/farmacologia , Streptomyces/metabolismo , Antineoplásicos/isolamento & purificação , Benzoxazóis/química , Benzoxazóis/isolamento & purificação , Linhagem Celular Tumoral , Humanos , Estrutura Molecular , Streptomyces/químicaRESUMO
A family of three novel aminofuran antibiotics named as proximicins was isolated from the marine Verrucosispora strain MG-37. Proximicin A was detected in parallel in the marine abyssomicin producer "Verrucosispora maris" AB-18-032. The characteristic structural element of proximicins is 4-amino-furan-2-carboxylic acid, a hitherto unknown gamma-amino acid. Proximicins show a weak antibacterial activity but a strong cytostatic effect to various human tumor cell lines.
Assuntos
Actinobacteria/metabolismo , Antibacterianos/farmacologia , Antibióticos Antineoplásicos/farmacologia , Netropsina/análogos & derivados , Actinobacteria/química , Actinobacteria/classificação , Antibacterianos/biossíntese , Antibacterianos/isolamento & purificação , Antibióticos Antineoplásicos/biossíntese , Antibióticos Antineoplásicos/isolamento & purificação , Bactérias/efeitos dos fármacos , Linhagem Celular Tumoral , Fenômenos Químicos , Físico-Química , Cromatografia Líquida de Alta Pressão , Fermentação , Humanos , Testes de Sensibilidade Microbiana , Netropsina/biossíntese , Netropsina/isolamento & purificação , Netropsina/farmacologia , Espectrofotometria UltravioletaRESUMO
The emergence of antibiotic resistant H. pylori strains has necessitated the identification of alternative additive therapies for the treatment of this infection. The study tested whether a specific pine bark extract (Pycnogenol is effective in inhibiting the growth and adherence of H. pylori in vitro. Inhibition of H. pylori growth by Pycnogenol was tested in liquid medium as well as in an in vitro model by using sessile bacteria attached to AGS cells. Adherence was determined by co-incubation of gastric cells with Pycnogenol and H. pylori in vitro. Pycnogenol inhibited H. pylori growth in suspension with an MIC(50) of 12.5 microg/mL. Growth of H. pylori in infected cells was reduced to 10% of the control value by 125 microg/mL Pycnogenol. Adherence of H. pylori to gastric cells was reduced by 70% after 3 h incubation with 125 microg/mL Pycnogenol. The results show a significant, yet limited inhibition of growth and adherence of H. pylori to gastric cells by Pycnogenol. In vivo studies have to demonstrate the clinical relevance of these findings.
Assuntos
Aderência Bacteriana/efeitos dos fármacos , Flavonoides/farmacologia , Mucosa Gástrica/microbiologia , Helicobacter pylori/efeitos dos fármacos , Linhagem Celular , Mucosa Gástrica/citologia , Helicobacter pylori/crescimento & desenvolvimento , Humanos , Testes de Sensibilidade Microbiana , Extratos VegetaisRESUMO
Two new aminophenoxazinone compounds with antitumor activity, elloxazinone A and B, were isolated from the culture filtrate of Streptomyces griseus Acta 2871. Their chemical structures were determined by mass spectrometry, NMR spectroscopy and X-ray analysis. Elloxazinones A and B showed a moderate inhibition of the proliferation of human cells from gastric adenocarcinoma in vitro but a strong inhibition of hepatocellular carcinoma cells whereas elloxazinone B strongly inhibited the proliferation of human breast carcinoma cells.
Assuntos
Antibióticos Antineoplásicos/isolamento & purificação , Oxazinas/isolamento & purificação , Streptomyces griseus/metabolismo , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Fermentação , Humanos , Espectroscopia de Ressonância Magnética , Oxazinas/química , Oxazinas/farmacologia , Streptomyces griseus/classificação , Relação Estrutura-AtividadeRESUMO
The addition of anthranilic acid to the culture medium of the marine derived Halomonas sp. strain GWS-BW-H8hM completely altered the secondary metabolite pattern relative to the standard conditions. The red-orange color of the culture filtrate extract was the result of the production of 2-aminophenoxazin-3-one (1), chandrananimycin C (5) and three new derivatives of 1 with a previously unknown substitution pattern: 2-amino-, 2-amino-8-benzoyl-, and 2-amino-8-(4-hydroxybenzoyl)-6-hydroxyphenoxazin-3-one (2-4). The compounds were determined to have antibacterial and cytotoxic activities; a mode of action other than DNA intercalation is discussed.
Assuntos
Antibacterianos/farmacologia , Candida albicans/efeitos dos fármacos , Gammaproteobacteria/metabolismo , Bactérias Gram-Positivas/efeitos dos fármacos , Oxazinas/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/metabolismo , Toxinas Bacterianas/metabolismo , Toxinas Bacterianas/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Gammaproteobacteria/crescimento & desenvolvimento , Humanos , Testes de Sensibilidade Microbiana , Oxazinas/química , Oxazinas/isolamento & purificação , Oxazinas/metabolismoRESUMO
Three new members of the fluostatin family, fluostatins C-E, were discovered in a culture filtrate extract of strain Acta 1383 during an HPLC screening program. The producing strain belongs to the genus Streptomyces and is closely related to type strains classified in the Streptomyces lavendulae 16S rRNA subclade. Fluostatins are named by their characteristic fluorenone chromophore. Fluostatin C shows moderate activity against selected human tumor cell lines.
Assuntos
Antineoplásicos/isolamento & purificação , Fluorenos/isolamento & purificação , Streptomyces/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Fluorenos/química , Fluorenos/farmacologia , Humanos , Estrutura Molecular , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria UltravioletaRESUMO
A new xanthone compound named retymicin (1) was isolated together with galtamycin B (2) and saquayamycin Z (3), new members of the galtamycin and saquayamycin families, respectively, and the new lumichrome derivative 1-(alpha-ribofuranosyl)-lumichrome (4) from Micromonospora strain Tü 6368, isolated from a soil sample collected in Romania. Retymicin, galtamycin B and saquayamycin Z show cytostatic effects to various human tumor cell lines whereas saquayamycin Z is also active against Gram-positive bacteria.
Assuntos
Antraciclinas/isolamento & purificação , Antraciclinas/farmacologia , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Antibióticos Antineoplásicos/isolamento & purificação , Antibióticos Antineoplásicos/farmacologia , Micromonospora/química , Xantonas/isolamento & purificação , Bactérias/efeitos dos fármacos , Sequência de Carboidratos , Linhagem Celular Tumoral , Fenômenos Químicos , Físico-Química , Cromatografia Líquida de Alta Pressão , Ensaios de Seleção de Medicamentos Antitumorais , Fermentação , Humanos , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Dados de Sequência Molecular , Romênia , Microbiologia do Solo , Xantonas/farmacologiaRESUMO
Scopolines 4 and the noradamantane scaffold are accessible from 8-oxabicyclo[3.2.1]oct-6-en-3-ones such as 6 by a concise route involving introduction of an axial amino nitrogen at C3, epoxidation, and cyclization. The resulting cage molecules are versatile drug leads.
Assuntos
Adamantano/química , Alcaloides/síntese químicaRESUMO
Glucocorticoids are effective agents in the management of inflammatory bowel diseases. However, information about their effects on repair mechanisms of the intestinal epithelium is incomplete.Therefore, the aim was to analyse in vitro effects of glucocorticoids on proliferation, restitution, and apoptosis as well as their effects on activity and expression of nuclear factor (NF)-kappaB, a known regulator of apoptosis and inflammation, in intestinal epithelial cells.Non-transformed rat jejunum epithelial cells (IEC-6) were cultured in the presence and absence of various concentrations of prednisolone and budesonide. IEC-6 cell proliferation was assessed by [3H]-thymidine incorporation. Restitution was analysed by an IEC-6 in vitro assay. Apoptosis was evaluated by ELISA and fluorescence microscopy. DNA binding activity and nuclear expression of NF-kappaB was determined by electrophoretic mobility shift assays and Western blotting, respectively. Prednisolone and budesonide stimulated IEC-6 cell proliferation at low to medium pharmacologic concentrations (prednisolone: 10(-9) to 10(-6) M; budesonide: 10(-11) to 10(-8) M). In contrast, high concentrations (>5 x 10(-5) M) had inhibitory effects on proliferation. 10(-7) M prednisolone and 10(-8) M budesonide increased restitution of IEC-6 cells, whereas high concentrations (10(-4) M) of prednisolone and budesonide decreased restitution. Apoptosis of IEC-6 cells was substantially enhanced by 10(-4) M budesonide; apoptosis was slightly increased by the highest prednisolone concentration used (5 x 10(-4) M). Furthermore, both glucocorticoids inhibited DNA binding activity and nuclear NF-kappaB expression in IEC-6 cells in a dose- and time-dependent fashion. In conclusion, prednisolone and budesonide modulate repair mechanisms of intestinal epithelial cells in vitro in a dose-dependent manner and profoundly modulate the inflammatory regulator NF-kappaB.
Assuntos
Glucocorticoides/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , NF-kappa B/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Budesonida/farmacologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular , DNA/biossíntese , DNA/metabolismo , Ensaio de Desvio de Mobilidade Eletroforética , Mucosa Intestinal/citologia , Mucosa Intestinal/patologia , Prednisolona/farmacologia , Ligação Proteica/efeitos dos fármacos , Ratos , Estatísticas não Paramétricas , Timidina/metabolismo , Cicatrização/efeitos dos fármacosRESUMO
The marine Microbacterium species HP2 (DSM 12583), isolated from the sponge Halichondria panicea, is able to produce a glucosylmannosyl-glycerolipid when grown on a complex medium with glucose. Optimizing the carbon sources in shake flask experiments has shown that glycerol affords the highest specific glycoglycerolipid production. The product yield approached 300 mg/L or 25 mg/g biomass upon scaling up in a 40-L bioreactor volume. The native diglycosyl-glycerolipid GGL.2 strongly inhibited growth of the tumor cell lines HM02 and Hep G2 (50% inhibition at 0.4 to 3 microg/mL), while the related deacylated compound (GG.2) showed a potent anti-tumor-promoting activity.
Assuntos
Antineoplásicos/farmacologia , Reatores Biológicos , Glicolipídeos/isolamento & purificação , Glicolipídeos/farmacologia , Micrococcaceae/química , Poríferos/microbiologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Glicolipídeos/biossínteseRESUMO
Strain Tü 6239 was isolated from a soil sample collected in Brazil and determined as a new species of the genus Streptomyces. In the course of our HPLC-diode array screening program three metabolites were detected in the culture filtrate and mycelium extracts of strain Tü 6239. They were characterised as members of the macrolactam group, the new compound ripromycin (1), the previously described ikarugamycin (2) and a new derivative of it, ikarugamycin epoxide (3). They show antibiotic activities against gram-positive bacteria and cytostatic effects to various human tumor cell lines.
Assuntos
Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Lactamas/isolamento & purificação , Lactamas/farmacologia , Compostos Policíclicos/isolamento & purificação , Compostos Policíclicos/farmacologia , Streptomyces/metabolismo , Antibacterianos/química , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/isolamento & purificação , Antibióticos Antineoplásicos/farmacologia , Cromatografia Líquida de Alta Pressão , Ensaios de Seleção de Medicamentos Antitumorais , Fermentação , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Lactamas/química , Macrolídeos , Testes de Sensibilidade Microbiana , Compostos Policíclicos/química , Microbiologia do Solo , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Streptomyces/química , Streptomyces/classificação , Células Tumorais CultivadasRESUMO
A new secondary metabolite was detected in the culture extract of Streptomyces sp. AK 409 by HPLC-diode-array screening. The metabolite was identified as pyrocoll, which is known to be a constituent of cigarette smoke. Pyrocoll is known as a synthetic compound, but until now had not been isolated as a natural product from a microorganism. The compound showed biological activity against various Arthrobacter strains, filamentous fungi, several pathogenic protozoa, and some human tumor cell lines.
Assuntos
Antibióticos Antineoplásicos/isolamento & purificação , Antiprotozoários/isolamento & purificação , Pirróis/isolamento & purificação , Streptomyces/metabolismo , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Antiprotozoários/química , Antiprotozoários/farmacologia , Cromatografia em Gel , Cromatografia Líquida de Alta Pressão , Ensaios de Seleção de Medicamentos Antitumorais , Fermentação , Células HeLa , Humanos , Espectrometria de Massas , Camundongos , Testes de Sensibilidade Microbiana , Ressonância Magnética Nuclear Biomolecular , Pirróis/farmacologia , Microbiologia do Solo , Espectrofotometria Infravermelho , Streptomyces/químicaRESUMO
Aspochalamins A-D, a family of new cytochalasan antibiotics have been isolated from Aspergillus niveus, an endosymbiotic fungus isolated from the gut of a woodlouse belonging to the family Trichoniscidae. Besides aspochalamins, aspochalasin Z, a new member of the aspochalasin family, as well as the known mycotoxins aspochalasin D and citreoviridins A/C and B were isolated from the mycelium. Aspochalamins showed cytostatic effects towards various tumor cell lines and a weak antibacterial activity against Gram-positive bacteria.
Assuntos
Antibacterianos/biossíntese , Antibacterianos/farmacologia , Aspergillus/metabolismo , Citocalasinas/biossíntese , Citocalasinas/farmacologia , Antibacterianos/química , Antibióticos Antineoplásicos/biossíntese , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Aspergillus/classificação , Bactérias/efeitos dos fármacos , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Citocalasinas/química , Ensaios de Seleção de Medicamentos Antitumorais , Fermentação , Humanos , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Espectrofotometria UltravioletaAssuntos
Antineoplásicos/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Netropsina/análogos & derivados , Netropsina/farmacologia , Proteína Supressora de Tumor p53/genética , Regulação para Cima/efeitos dos fármacos , Actinobacteria/química , Furanos , Estrutura Molecular , Netropsina/química , Netropsina/isolamento & purificaçãoRESUMO
There is increasing evidence that tyrosine kinase inhibitors (TKIs) have significant blood glucose lowering effects. A 70-year old Caucasian male with liver cirrhosis Child-Pugh A, advanced hepatocellular carcinoma and diabetes had a stable glycemic control being treated with glibenclamide (3.5 mg twice daily). After the first daily dose of the TKI sorafenib (800 mg) the patient experienced acute nocturnal disorientation and somnolence with a corresponding blood glucose of 37 mg/dl. After administration of glucose intravenously the neurological disturbances were completely reversible. As there was no intercurrent deterioration neither of hepatic nor of renal function, the severe hypoglycemia can likely be attributed to a drug-drug interaction of sorafenib with the sulfonylurea. The complete inhibition of the CYP2C9 and CYP3A4 mediated metabolic pathway of glibenclamide through sorafenib might have resulted in a rapid accumulation of glibenclamide. Profound blood glucose lowering effects of sorafenib might have additionally contributed to the hypoglycemic episode.
Assuntos
Glibureto/efeitos adversos , Hipoglicemia/induzido quimicamente , Niacinamida/análogos & derivados , Compostos de Fenilureia/efeitos adversos , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Glicemia/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Interações Medicamentosas , Glibureto/uso terapêutico , Humanos , Hipoglicemia/fisiopatologia , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Niacinamida/efeitos adversos , Niacinamida/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Índice de Gravidade de Doença , SorafenibeRESUMO
INTRODUCTION: The cytochrome P4502C enzymes account for the metabolism of approximately 20% of therapeutic drugs including certain oral antidiabetic drugs (OADs). AREAS COVERED: This review focuses on the effect of CYP2C enzymes on metabolism of sulphonylureas (SUs), meglitinides, and thiazolidinediones (TZDs) discussing their impact on pharmacokinetics, drug interactions and toxicological profiles. Pharmacogenetic aspects reflecting individual gene variants and variable drug effects are also considered. EXPERT OPINION: Genetic polymorphisms of CYP2C9 enzymes (*2/*2, *2/*3, *3/*3) influence the glycaemic response to SUs and impair their substrate metabolism. Restricted data from small-sized studies with heterogenous definitions of hypoglycaemia revealed no clear association between CYP2C9 genotypes and the risk of hypoglycaemia. Functional polymorphisms of CYP2C8- and CYP2C9 drug metabolizing genes affect markedly pharmacokinetics of meglitinides. Compared to wild-type carriers, patients treated with TZDs and carrying the common CYP2C8*3 and *4 variants showed a reduced glycaemic control. The strong CYP2C8 and OATP1B1 inhibitor gemfibrozil increases substantially the plasma concentrations of repaglinide and TZDs. Numerous metabolic drug interactions exist between SUs and commonly prescribed drugs, especially anti-infectives. The complex pharmacokinetic and pharmacogenetic properties and the unfavourable short and long term risk profile of glibenclamide and glimepiride raise the question whether their use can be justified any longer.