rifampin has been researched along with Carcinoma--Hepatocellular* in 26 studies
1 review(s) available for rifampin and Carcinoma--Hepatocellular
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Impact of dexamethasone and tocilizumab on hematological parameters in COVID-19 patients with chronic disease.
The most effective way to control severity and mortality rate of the novel coronavirus disease (COVID-19) is through sensitive diagnostic approaches and an appropriate treatment protocol. We aimed to identify the effect of adding corticosteroid and Tocilizumab to a standard treatment protocol in treating COVID-19 patients with chronic disease through hematological and lab biomarkers.. This study was performed retrospectively on 68 COVID-19 patients with chronic disease who were treated by different therapeutic protocols. The patients were categorized into four groups: control group represented the patients' lab results at admission before treatment protocols were applied; group 1 included patients treated with anticoagulants, Hydroxychloroquine, and antibiotics; group 2 comprised patients treated with Dexamethasone; and group 3 included patients treated with Dexamethasone and Tocilizumab.. The study paves the way into the effectiveness of combining Dexamethasone with Tocilizumab in treatment COVID-19 patients with chronic diseases.. La forma más eficaz de controlar la gravedad y la tasa de mortalidad de la enfermedad del nuevo coronavirus (COVID-19) es mediante enfoques de diagnóstico sensibles y un protocolo de tratamiento adecuado. Nuestro objetivo fue identificar el efecto de agregar corticosteroides y tocilizumab a un protocolo de tratamiento estándar en el tratamiento de pacientes con COVID-19 con enfermedad crónica a través de biomarcadores hematológicos y de laboratorio.. Este estudio se realizó de forma retrospectiva en 68 pacientes COVID-19 con enfermedad crónica que fueron tratados por diferentes protocolos terapéuticos. Los pacientes se clasificaron en cuatro grupos: el grupo de control representaba los resultados de laboratorio de los pacientes en el momento de la admisión antes de que se aplicaran los protocolos de tratamiento; el grupo 1 incluyó a pacientes tratados con anticoagulantes, hidroxicloroquina y antibióticos; el grupo 2 estaba compuesto por pacientes tratados con dexametasona; y el grupo 3 incluyó a pacientes tratados con dexametasona y tocilizumab.. El estudio allana el camino hacia la eficacia de la combinación de dexametasona con tocilizumab en el tratamiento de pacientes con COVID-19 con enfermedades crónicas.. The Child-Mother Index constitutes a potential useful risk factor indicator for statistical analyses on data after birth. The value of the Child-Mother Index based on the estimated fetal weight before birth deserves evaluation.. Six ceria supports synthesized by various synthesis methodologies were used to deposit cobalt oxide. The catalysts were thoroughly characterized, and their catalytic activity for complete methane oxidation was studied. The supports synthesized by direct calcination and precipitation with ammonia exhibited the best textural and structural properties as well as the highest degree of oxidation. The remaining supports presented poorer textural properties to be employed as catalytic supports. The cobalt deposited over the first two supports presented a good dispersion at the external surface, which induced a significant redox effect that increased the number of Co. Some studies show that children with obesity are more likely to receive a diagnosis of depression, anxiety, or attention-deficit hyperactivity disorder (ADHD). But this does not necessarily mean obesity causes these conditions. Depression, anxiety, or ADHD could cause obesity. A child's environment, including family income or their parents' mental health, could also affect a child's weight and mental health. Understanding the nature of these relationships could help scientists develop better interventions for both obesity and mental health conditions. Genetic studies may help scientists better understand the role of the environment in these conditions, but it's important to consider both the child's and their parents’ genetics in these analyses. This is because parents and children share not only genes, but also environmental conditions. For example, families that carry genetic variants associated with higher body weight might also have lower incomes, if parents have been affected by biases against heavier people in society and the workplace. Children in these families could have worse mental health because of effects of their parent’s weight, rather than their own weight. Looking at both child and adult genetics can help disentangle these processes. Hughes et al. show that a child's own body mass index, a ratio of weight and height, is not strongly associated with the child’s mental health symptoms. They analysed genetic, weight, and health survey data from about 41,000 8-year-old children and their parents. The results suggest that a child's own BMI does not have a large effect on their anxiety symptoms. There was also no clear evidence that a child's BMI affected their symptoms of depression or ADHD. These results contradict previous studies, which did not account for parental genetics. Hughes et al. suggest that, at least for eight-year-olds, factors linked with adult weight and which differ between families may be more critical to a child's mental health than a child’s own weight. For older children and adolescents, this may not be the case, and the individual’s own weight may be more important. As a result, policies designed to reduce obesity in mid-childhood are unlikely to greatly improve the mental health of children. On the other hand, policies targeting the environmental or societal factors contributing to higher body weights, bias against people with higher weights, and poor child mental health directly may be more beneficial.. The development of an efficient photocatalyst for C2 product formation from CO. Оценка антиастенического эффекта последовательной терапии левокарнитином (ЛК) и ацетилкарнитином (АЛК) пациентов с артериальной гипертензией и/или ишемической болезнью сердца (ИБС) с астеническим синдромом (АС).. В открытое сравнительное исследование были включены 120 пациентов в возрасте 54—67 лет с артериальной гипертензией и/или ИБС с АС. Пациенты 1-й группы (. У больных 1-й группы отмечено статистически значимое уменьшение различных проявлений АС. Отличия носили достоверный характер по сравнению как с исходным уровнем, так и со 2-й группой. Установлено эндотелийпротективное действие ЛК и АЛК.. Полученные результаты свидетельствуют, что у таких коморбидных пациентов использование ЛК и АЛК уменьшает выраженность проявлений АС, а установленные эндотелиотропные свойства препаратов позволяют рекомендовать их в составе комплексной персонифицированной терапии пациентов с сердечно-сосудистыми заболеваниями.. Naproxen sodium 440 mg/diphenhydramine 50 mg combination demonstrated improvement in sleep maintenance (WASO) vs. naproxen sodium 550 mg and higher efficiency in average daily pain reduction compared with the comparison groups. The treatment was well tolerated There were no serious or unexpected adverse events reported in the study.. Сравнительный анализ эффективности и безопасности новой комбинации напроксена натрия и дифенгидрамина у пациентов с неспецифическим болевым синдромом в пояснично-крестцовом отделе спины (M54.5 «Боль внизу спины») и нарушением сна (G47.0 «Нарушения засыпания и поддержания сна [бессонница]»).. Проведено проспективное многоцентровое рандомизированное открытое сравнительное в параллельных группах клиническое исследование. Пациенты были рандомизированы в 3 группы. Больные 1-й группы получали напроксен натрия (440 мг) и дифенгидрамин (50 мг), 2-й — напроксен натрия (550 мг), 3-й — парацетамол (1000 мг) и дифенгидрамин (50 мг). Исследуемые препараты пациенты принимали однократно перед сном в течение 3 дней. Все пациенты также принимали 275 мг (1 таблетка) напроксена натрия в качестве препарата фоновой терапии. Первичным критерием эффективности было общее время бодрствования после наступления сна (WASO), измеряемое методом актиграфии. Также использовались критерии оценки продолжительности и качества сна и выраженности боли.. Анализ эффективности проведен для ITT популяции (. Применение комбинации напроксена натрия (440 мг) и дифенгидрамина (50 мг) характеризовалось более выраженным поддержанием сна по сравнению с напроксеном натрия 550 мг и более высокой эффективностью в отношении снижения интенсивности боли по сравнению со 2-й и 3-й группами. Отмечена хорошая переносимость препарата, серьезных нежелательных явлений зарегистрировано не было. Topics: Acetaminophen; Acetylcarnitine; Acetylcholinesterase; Acids; Acinetobacter baumannii; Acinetobacter Infections; Adaptation, Psychological; Adolescent; Adsorption; Adult; Aged; Alcohol Drinking; Alzheimer Disease; Amikacin; Ammonia; Anaerobiosis; Animals; Anorexia; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Anxiety; Aptamers, Nucleotide; Asthenia; Attention Deficit Disorder with Hyperactivity; Bacterial Proteins; Beryllium; beta-Lactamases; Biofuels; Biomass; Biosensing Techniques; Bismuth; Blister; Body Mass Index; Body Surface Area; Boronic Acids; Brain; Breast Neoplasms; Butyrylcholinesterase; Cannabis; Carbapenems; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Carboxylic Acids; Carcinoma, Hepatocellular; Cardiovascular Diseases; Carnitine; Case-Control Studies; Catalysis; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Child; China; Cholinesterase Inhibitors; Clarithromycin; Clostridioides; Clostridioides difficile; Clostridium Infections; Cohort Studies; Colistin; Colitis; Colon; Coloring Agents; Coronary Artery Bypass; Creatinine; Crystalloid Solutions; Cytokines; Depression; Dextran Sulfate; Dextrans; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Diarrhea; Dietary Supplements; Diphenhydramine; Disease Models, Animal; Disease Outbreaks; Double-Blind Method; Doxorubicin; Drosophila; Drug Tapering; Dysbiosis; Electrons; Escherichia coli; Extracellular Vesicles; Fatigue; Female; Fermentation; gamma-Cyclodextrins; Gastrointestinal Microbiome; Glucose; Graft Survival; Graft vs Host Disease; Head and Neck Neoplasms; Heart Arrest, Induced; Hematopoietic Stem Cell Transplantation; High-Intensity Interval Training; Hippocampus; Humans; Hydrogen-Ion Concentration; Hypertension; Incidence; Interferon-gamma; Italy; Kinetics; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Lactoferrin; Larva; Length of Stay; Lignin; Liver; Liver Neoplasms; Liver Transplantation; Living Donors; Low Back Pain; Lung; Lung Volume Measurements; Macrophages; Male; Melphalan; Men; Mendelian Randomization Analysis; Meropenem; Methane; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Mitochondrial Proteins; Molecular Docking Simulation; Molecular Structure; Mothers; Motivation; Mycoplasma; Mycoplasma hominis; Mycoplasma Infections; NAD; Nanocomposites; Nanoparticles; Nanotubes, Carbon; Naproxen; Neovascularization, Pathologic; Neurons; Nitrates; Nucleolin; Opuntia; Paratyphoid Fever; Phenotype; Phosphatidylinositol 3-Kinases; Phytochemicals; Plant Extracts; Pregnancy; Prevalence; Prospective Studies; Proto-Oncogene Proteins c-akt; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Wistar; Resveratrol; Retrospective Studies; Rifampin; Risk Factors; RNA, Messenger; Selenium; Sleep; Social Behavior; Soil; Soil Pollutants; Squamous Cell Carcinoma of Head and Neck; Staphylococcus aureus; Structure-Activity Relationship; Suicidal Ideation; Suicide; Superoxide Dismutase-1; Surveys and Questionnaires; Swimming; Syndrome; Tannins; Temperature; Transforming Growth Factor beta; Transplantation Conditioning; Treatment Outcome; Triple Negative Breast Neoplasms; Troponin T; Tumor Microenvironment; United Kingdom; Ureaplasma; Ureaplasma urealyticum; Urinary Tract Infections; Viscum; Waste Disposal Facilities; Wastewater; Water; Water Pollutants, Chemical; Wolfiporia; Young Adult | 2022 |
1 trial(s) available for rifampin and Carcinoma--Hepatocellular
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Impact of dexamethasone and tocilizumab on hematological parameters in COVID-19 patients with chronic disease.
The most effective way to control severity and mortality rate of the novel coronavirus disease (COVID-19) is through sensitive diagnostic approaches and an appropriate treatment protocol. We aimed to identify the effect of adding corticosteroid and Tocilizumab to a standard treatment protocol in treating COVID-19 patients with chronic disease through hematological and lab biomarkers.. This study was performed retrospectively on 68 COVID-19 patients with chronic disease who were treated by different therapeutic protocols. The patients were categorized into four groups: control group represented the patients' lab results at admission before treatment protocols were applied; group 1 included patients treated with anticoagulants, Hydroxychloroquine, and antibiotics; group 2 comprised patients treated with Dexamethasone; and group 3 included patients treated with Dexamethasone and Tocilizumab.. The study paves the way into the effectiveness of combining Dexamethasone with Tocilizumab in treatment COVID-19 patients with chronic diseases.. La forma más eficaz de controlar la gravedad y la tasa de mortalidad de la enfermedad del nuevo coronavirus (COVID-19) es mediante enfoques de diagnóstico sensibles y un protocolo de tratamiento adecuado. Nuestro objetivo fue identificar el efecto de agregar corticosteroides y tocilizumab a un protocolo de tratamiento estándar en el tratamiento de pacientes con COVID-19 con enfermedad crónica a través de biomarcadores hematológicos y de laboratorio.. Este estudio se realizó de forma retrospectiva en 68 pacientes COVID-19 con enfermedad crónica que fueron tratados por diferentes protocolos terapéuticos. Los pacientes se clasificaron en cuatro grupos: el grupo de control representaba los resultados de laboratorio de los pacientes en el momento de la admisión antes de que se aplicaran los protocolos de tratamiento; el grupo 1 incluyó a pacientes tratados con anticoagulantes, hidroxicloroquina y antibióticos; el grupo 2 estaba compuesto por pacientes tratados con dexametasona; y el grupo 3 incluyó a pacientes tratados con dexametasona y tocilizumab.. El estudio allana el camino hacia la eficacia de la combinación de dexametasona con tocilizumab en el tratamiento de pacientes con COVID-19 con enfermedades crónicas.. The Child-Mother Index constitutes a potential useful risk factor indicator for statistical analyses on data after birth. The value of the Child-Mother Index based on the estimated fetal weight before birth deserves evaluation.. Six ceria supports synthesized by various synthesis methodologies were used to deposit cobalt oxide. The catalysts were thoroughly characterized, and their catalytic activity for complete methane oxidation was studied. The supports synthesized by direct calcination and precipitation with ammonia exhibited the best textural and structural properties as well as the highest degree of oxidation. The remaining supports presented poorer textural properties to be employed as catalytic supports. The cobalt deposited over the first two supports presented a good dispersion at the external surface, which induced a significant redox effect that increased the number of Co. Some studies show that children with obesity are more likely to receive a diagnosis of depression, anxiety, or attention-deficit hyperactivity disorder (ADHD). But this does not necessarily mean obesity causes these conditions. Depression, anxiety, or ADHD could cause obesity. A child's environment, including family income or their parents' mental health, could also affect a child's weight and mental health. Understanding the nature of these relationships could help scientists develop better interventions for both obesity and mental health conditions. Genetic studies may help scientists better understand the role of the environment in these conditions, but it's important to consider both the child's and their parents’ genetics in these analyses. This is because parents and children share not only genes, but also environmental conditions. For example, families that carry genetic variants associated with higher body weight might also have lower incomes, if parents have been affected by biases against heavier people in society and the workplace. Children in these families could have worse mental health because of effects of their parent’s weight, rather than their own weight. Looking at both child and adult genetics can help disentangle these processes. Hughes et al. show that a child's own body mass index, a ratio of weight and height, is not strongly associated with the child’s mental health symptoms. They analysed genetic, weight, and health survey data from about 41,000 8-year-old children and their parents. The results suggest that a child's own BMI does not have a large effect on their anxiety symptoms. There was also no clear evidence that a child's BMI affected their symptoms of depression or ADHD. These results contradict previous studies, which did not account for parental genetics. Hughes et al. suggest that, at least for eight-year-olds, factors linked with adult weight and which differ between families may be more critical to a child's mental health than a child’s own weight. For older children and adolescents, this may not be the case, and the individual’s own weight may be more important. As a result, policies designed to reduce obesity in mid-childhood are unlikely to greatly improve the mental health of children. On the other hand, policies targeting the environmental or societal factors contributing to higher body weights, bias against people with higher weights, and poor child mental health directly may be more beneficial.. The development of an efficient photocatalyst for C2 product formation from CO. Оценка антиастенического эффекта последовательной терапии левокарнитином (ЛК) и ацетилкарнитином (АЛК) пациентов с артериальной гипертензией и/или ишемической болезнью сердца (ИБС) с астеническим синдромом (АС).. В открытое сравнительное исследование были включены 120 пациентов в возрасте 54—67 лет с артериальной гипертензией и/или ИБС с АС. Пациенты 1-й группы (. У больных 1-й группы отмечено статистически значимое уменьшение различных проявлений АС. Отличия носили достоверный характер по сравнению как с исходным уровнем, так и со 2-й группой. Установлено эндотелийпротективное действие ЛК и АЛК.. Полученные результаты свидетельствуют, что у таких коморбидных пациентов использование ЛК и АЛК уменьшает выраженность проявлений АС, а установленные эндотелиотропные свойства препаратов позволяют рекомендовать их в составе комплексной персонифицированной терапии пациентов с сердечно-сосудистыми заболеваниями.. Naproxen sodium 440 mg/diphenhydramine 50 mg combination demonstrated improvement in sleep maintenance (WASO) vs. naproxen sodium 550 mg and higher efficiency in average daily pain reduction compared with the comparison groups. The treatment was well tolerated There were no serious or unexpected adverse events reported in the study.. Сравнительный анализ эффективности и безопасности новой комбинации напроксена натрия и дифенгидрамина у пациентов с неспецифическим болевым синдромом в пояснично-крестцовом отделе спины (M54.5 «Боль внизу спины») и нарушением сна (G47.0 «Нарушения засыпания и поддержания сна [бессонница]»).. Проведено проспективное многоцентровое рандомизированное открытое сравнительное в параллельных группах клиническое исследование. Пациенты были рандомизированы в 3 группы. Больные 1-й группы получали напроксен натрия (440 мг) и дифенгидрамин (50 мг), 2-й — напроксен натрия (550 мг), 3-й — парацетамол (1000 мг) и дифенгидрамин (50 мг). Исследуемые препараты пациенты принимали однократно перед сном в течение 3 дней. Все пациенты также принимали 275 мг (1 таблетка) напроксена натрия в качестве препарата фоновой терапии. Первичным критерием эффективности было общее время бодрствования после наступления сна (WASO), измеряемое методом актиграфии. Также использовались критерии оценки продолжительности и качества сна и выраженности боли.. Анализ эффективности проведен для ITT популяции (. Применение комбинации напроксена натрия (440 мг) и дифенгидрамина (50 мг) характеризовалось более выраженным поддержанием сна по сравнению с напроксеном натрия 550 мг и более высокой эффективностью в отношении снижения интенсивности боли по сравнению со 2-й и 3-й группами. Отмечена хорошая переносимость препарата, серьезных нежелательных явлений зарегистрировано не было. Topics: Acetaminophen; Acetylcarnitine; Acetylcholinesterase; Acids; Acinetobacter baumannii; Acinetobacter Infections; Adaptation, Psychological; Adolescent; Adsorption; Adult; Aged; Alcohol Drinking; Alzheimer Disease; Amikacin; Ammonia; Anaerobiosis; Animals; Anorexia; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Anxiety; Aptamers, Nucleotide; Asthenia; Attention Deficit Disorder with Hyperactivity; Bacterial Proteins; Beryllium; beta-Lactamases; Biofuels; Biomass; Biosensing Techniques; Bismuth; Blister; Body Mass Index; Body Surface Area; Boronic Acids; Brain; Breast Neoplasms; Butyrylcholinesterase; Cannabis; Carbapenems; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Carboxylic Acids; Carcinoma, Hepatocellular; Cardiovascular Diseases; Carnitine; Case-Control Studies; Catalysis; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Child; China; Cholinesterase Inhibitors; Clarithromycin; Clostridioides; Clostridioides difficile; Clostridium Infections; Cohort Studies; Colistin; Colitis; Colon; Coloring Agents; Coronary Artery Bypass; Creatinine; Crystalloid Solutions; Cytokines; Depression; Dextran Sulfate; Dextrans; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Diarrhea; Dietary Supplements; Diphenhydramine; Disease Models, Animal; Disease Outbreaks; Double-Blind Method; Doxorubicin; Drosophila; Drug Tapering; Dysbiosis; Electrons; Escherichia coli; Extracellular Vesicles; Fatigue; Female; Fermentation; gamma-Cyclodextrins; Gastrointestinal Microbiome; Glucose; Graft Survival; Graft vs Host Disease; Head and Neck Neoplasms; Heart Arrest, Induced; Hematopoietic Stem Cell Transplantation; High-Intensity Interval Training; Hippocampus; Humans; Hydrogen-Ion Concentration; Hypertension; Incidence; Interferon-gamma; Italy; Kinetics; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Lactoferrin; Larva; Length of Stay; Lignin; Liver; Liver Neoplasms; Liver Transplantation; Living Donors; Low Back Pain; Lung; Lung Volume Measurements; Macrophages; Male; Melphalan; Men; Mendelian Randomization Analysis; Meropenem; Methane; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Mitochondrial Proteins; Molecular Docking Simulation; Molecular Structure; Mothers; Motivation; Mycoplasma; Mycoplasma hominis; Mycoplasma Infections; NAD; Nanocomposites; Nanoparticles; Nanotubes, Carbon; Naproxen; Neovascularization, Pathologic; Neurons; Nitrates; Nucleolin; Opuntia; Paratyphoid Fever; Phenotype; Phosphatidylinositol 3-Kinases; Phytochemicals; Plant Extracts; Pregnancy; Prevalence; Prospective Studies; Proto-Oncogene Proteins c-akt; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Wistar; Resveratrol; Retrospective Studies; Rifampin; Risk Factors; RNA, Messenger; Selenium; Sleep; Social Behavior; Soil; Soil Pollutants; Squamous Cell Carcinoma of Head and Neck; Staphylococcus aureus; Structure-Activity Relationship; Suicidal Ideation; Suicide; Superoxide Dismutase-1; Surveys and Questionnaires; Swimming; Syndrome; Tannins; Temperature; Transforming Growth Factor beta; Transplantation Conditioning; Treatment Outcome; Triple Negative Breast Neoplasms; Troponin T; Tumor Microenvironment; United Kingdom; Ureaplasma; Ureaplasma urealyticum; Urinary Tract Infections; Viscum; Waste Disposal Facilities; Wastewater; Water; Water Pollutants, Chemical; Wolfiporia; Young Adult | 2022 |
25 other study(ies) available for rifampin and Carcinoma--Hepatocellular
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Long Noncoding RNAs Hepatocyte Nuclear Factor 4A Antisense RNA 1 and Hepatocyte Nuclear Factor 1A Antisense RNA 1 Are Involved in Ritonavir-Induced Cytotoxicity in Hepatoma Cells.
Ritonavir (RTV), a pharmacoenhancer used in anti-HIV regimens, can induce liver damage. RTV is primarily metabolized by cytochrome P450 3A4 (CYP3A4) in the liver. HNF4A antisense RNA 1 (HNF4A-AS1) and HNF1A antisense RNA 1 (HNF1A-AS1) are long noncoding RNAs that regulate the expression of pregnane X receptor (PXR) and CYP3A4. This study investigated the role and underlying mechanisms of HNF4A-AS1 and HNF1A-AS1 in RTV-induced hepatotoxicity. HNF4A-AS1 and HNF1A-AS1 were knocked down by small hairpin RNAs in Huh7 and HepG2 cells. Lactate dehydrogenase and reactive oxygen species assays were performed to assess RTV-induced hepatotoxicity. Chromatin immunoprecipitation quantitative real-time polymerase chain reaction was used to detect PXR enrichment and histone modifications in the CYP3A4 promoter. HNF4A-AS1 knockdown increased PXR and CYP3A4 expression and exacerbated RTV-induced cytotoxicity, whereas HNF1A-AS1 knockdown generated the opposite phenotype. Mechanistically, enrichment of PXR and trimethylation of histone 3 lysine 4 (H3K4me3) in the CYP3A4 promoter was increased, and trimethylation of histone 3 lysine 27 (H3K27me3) was decreased after HNF4A-AS1 knockdown. However, PXR and H3K4me3 enrichment decreased after HNF1A-AS1 knockdown. Alterations in RTV-induced hepatotoxicity caused by decreasing HNF4A-AS1 or HNF1A-AS1 were reversed by knockdown or overexpression of PXR. Increased susceptibility to RTV-induced liver injury caused by the PXR activator rifampicin was attenuated by HNF4A-AS1 overexpression or HNF1A-AS1 knockdown. Taken together, these results revealed that HNF4A-AS1 and HNF1A-AS1 modulated RTV-induced hepatotoxicity by regulating CYP3A4 expression, primarily by affecting the binding of PXR and histone modification status in the CYP3A4 promoter. SIGNIFICANCE STATEMENT: HNF4A-AS1 and HNF1A-AS1, transcribed separately from neighboring antisense genes of the human transcription factor genes Topics: Carcinoma, Hepatocellular; Chemical and Drug Induced Liver Injury, Chronic; Cytochrome P-450 CYP3A; Hepatocyte Nuclear Factor 1; Hepatocyte Nuclear Factor 4; Histones; Humans; Liver Neoplasms; Lysine; Receptors, Steroid; Rifampin; Ritonavir; RNA, Antisense; RNA, Long Noncoding | 2022 |
Hepatocellular Injury in Children Treated for Rifampicin-resistant Tuberculosis: Incidence, Etiology and Outcome.
Hepatocellular injury has been reported commonly in adults on rifampicin-resistant and multidrug-resistant tuberculosis (RR/MDR-TB) treatment. However, there are limited data in children.. Two pharmacokinetic studies of children (0-17 years) routinely treated for RR/MDR-TB were conducted in Cape Town, South Africa between October 2011 and February 2020. Hepatocellular injury adverse events (AEs; defined as elevated alanine aminotransferase [ALT]) were documented serially. Data were analyzed to determine the incidence, etiology, risk factors, management and outcome of ALT elevation.. A total of 217 children, median age 3.6 years (interquartile range, 1.7-7.1 years) at enrollment were included. The median follow-up time was 14.0 months (interquartile range, 9.8-17.2 months). Fifty-five (25.3%) patients developed an ALT AE. Of these, 43 of 55 (78%) patients had 54 ALT AEs attributed to their RR/MDR-TB treatment. The incidence rate of ALT AEs related to RR-TB treatment was 22.4 per 100 person-years. Positive HIV status and having an elevated ALT at enrollment were associated with time to ALT AE attributed to RR/MDR-TB treatment, with P values 0.0427 and P < 0.0001, respectively. Hepatitis A IgM was positive in 11 of 14 (78.6%) severe (grade ≥3) cases of ALT AEs. In 8 of 14 (57%) severe ALT AEs, hepatotoxic drugs were stopped or temporarily interrupted. None had a fatal or unresolved outcome.. Hepatocellular injury in children on RR/MDR-TB treatment is common, although usually mild; having elevated ALT early in treatment and HIV-positive status are possible risk factors. Hepatitis A was a common etiology of severe ALT AE in children treated for RR/MDR-TB. Topics: Adult; Antitubercular Agents; Carcinoma, Hepatocellular; Child; Child, Preschool; Hepatitis A; Humans; Incidence; Liver Neoplasms; Rifampin; South Africa; Treatment Outcome; Tuberculosis, Multidrug-Resistant | 2022 |
The Isoniazid Metabolites Hydrazine and Pyridoxal Isonicotinoyl Hydrazone Modulate Heme Biosynthesis.
In a mouse model, rifampicin and isoniazid combination treatment results in cholestatic liver injury that is associated with an increase in protoporphyrin IX, the penultimate heme precursor. Both ferrochelatase (FECH/Fech) and aminolevulinic acid synthase 1 (ALAS1/Alas1) are crucial enzymes in regulating heme biosynthesis. Isoniazid has recently been reported to upregulate Alas1 but downregulate Fech protein levels in mice; however, the mechanism by which isoniazid mediates disruption of heme synthesis has been unclear. Two metabolites of isoniazid, pyridoxal isonicotinoyl hydrazone (PIH, the isoniazid-vitamin B6 conjugate) and hydrazine, have been detected in the urine of humans treated with isoniazid. Here we show that, in primary human hepatocytes and the human hepatocellular carcinoma cell line HepG2/C3A, (1) isoniazid treatment increases Alas1 protein levels but decreases Fech levels; (2) hydrazine treatment upregulates Alas1 protein and Alas1 mRNA levels; (3) PIH treatment decreases Fech protein levels, but not Fech mRNA levels; and (4) PIH is detected after isoniazid treatment, with levels increasing further when exogenous vitamin B6 analogs are coadministered. In addition, the PIH-mediated downregulation of human FECH is associated with iron chelation. Together, these data demonstrate that hydrazine upregulates ALAS1, whereas PIH downregulates FECH, suggesting that the metabolites of isoniazid mediate its disruption of heme biosynthesis by contributing to protoporphyrin IX accumulation. Topics: 5-Aminolevulinate Synthetase; Animals; Carcinoma, Hepatocellular; Ferrochelatase; Heme; Hep G2 Cells; Hepatocytes; Humans; Hydrazines; Iron; Isoniazid; Liver; Mice, Inbred C57BL; Mice, Transgenic; Protoporphyrins; Pyridoxal; Rifampin; Vitamin B 6 | 2019 |
Functional polarization of human hepatoma HepaRG cells in response to forskolin.
HepaRG is an original human hepatoma cell line, acquiring highly differentiated hepatic features when exposed to dimethylsulfoxide (DMSO). To search alternatives to DMSO, which may exert some toxicity, we have analyzed the effects of forskolin (FSK), a cAMP-generating agent known to favor differentiation of various cell types. FSK used at 50 µM for 3 days was found to promote polarization of high density-plated HepaRG cells, i.e., it markedly enhanced the formation of functional biliary canaliculi structures. It also increased expressions of various hepatic markers, including those of cytochrome P-450 (CYP) 3A4, of drug transporters like NTCP, OATP2B1 and BSEP, and of metabolism enzymes like glucose 6-phosphatase. In addition, FSK-treated HepaRG cells displayed enhanced activities of CYP3A4, NTCP and OATPs when compared to untreated cells. These polarizing/differentiating effects of FSK were next shown to reflect not only the generation of cAMP, but also the activation of the xenobiotic sensing receptors PXR and FXR by FSK. Co-treatment of HepaRG cells by the cAMP analog Sp-5,6-DCl-cBIMPS and the reference PXR agonist rifampicin reproduced the polarizing effects of FSK. Therefore, FSK may be considered as a relevant alternative to DMSO for getting polarized and differentiated HepaRG cells, notably for pharmacological and toxicological studies. Topics: Bile Canaliculi; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Polarity; Colforsin; Cyclic AMP; Gene Expression Regulation, Neoplastic; Humans; Liver; Liver Neoplasms; Pregnane X Receptor; Rifampin; RNA, Messenger; Signal Transduction | 2018 |
Anti-tuberculosis treatments and risk of hepatocellular carcinoma in tuberculosis patients with liver cirrhosis: a population-based case-control study.
The objective of this study was to evaluate the association between the use of anti-tuberculosis (anti-TB) agents, isoniazid (INH), rifampicin (RIF), and their combination (INH + RIF), and the risk of hepatocellular carcinoma (HCC) in cirrhotic patients. This population-based case-control study was conducted using a research database of Taiwan's National Health Insurance program. Cirrhotic patients first diagnosed with HCC between 1996 and 2011 (n = 50,351), among whom 4,738 were anti-TB medication users, were evaluated. Cirrhotic patients who did not develop HCC within the same period, frequency-matched according to age, sex, and index year, were evaluated as the control group (n = 47,488). The adjusted odds ratio (OR) of HCC was 1.34 [95 % confidence interval (CI), 1.20-1.50] in INH + RIF users compared with non-INH + RIF users. Long-term (>12 months) use of INH, RIF, and INH + RIF was significantly associated with increased risk of HCC, with an adjusted OR of 3.51 (95 % CI, 2.11-5.84), 4.17 (95 % CI, 2.76-4.31), and 7.17 (95 % CI, 4.08-12.6), respectively, after adjusting for age, sex, and comorbidities. An average dose of INH + RIF >16,050 mg/year was associated with increased risk of HCC in cirrhotic patients, with an adjusted OR of 1.48 (95 % CI, 1.27-1.73). Our results indicate that cirrhotic patients with long-term or high-dose INH and RIF treatment, particularly their combination, are associated with increased risk of HCC development. Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Carcinoma, Hepatocellular; Case-Control Studies; Drug Therapy, Combination; Female; Humans; Isoniazid; Liver Cirrhosis; Male; Middle Aged; Rifampin; Risk; Risk Assessment; Taiwan; Tuberculosis; Young Adult | 2015 |
HepaRG cell line as an in vitro model for screening drug-drug interactions mediated by metabolic induction: amiodarone used as a model substance.
The prediction of drug-drug interactions mediated by the induction or inhibition of cytochrome P450 enzymes is of great relevance in the development of new drugs. Due to the fact that HepaRG, a new human cell line derived from a hepatocellular carcinoma, is being considered a promising model to evaluate the in vitro metabolism of drugs, it was herein used for investigating metabolic-based drug-drug interactions mediated by metabolic induction. In this study, rifampicin and phenytoin were used as probe inducers and amiodarone (AM) as a model drug. HepaRG cells were firstly seeded in the supplemented Williams' E, and then differentiated in the same culture medium, supplemented with 2% dimethyl sulfoxide for 2 weeks. For metabolic induction studies AM was incubated during 12h in HepaRG cells which were pre-incubated with phenytoin or rifampicin for 72 h. The concentrations of AM and its main metabolite, mono-N-desethylamiodarone, were quantified by HPLC-DAD. This study evidenced that rifampicin and phenytoin are powerful inducers of the metabolism of AM, including at therapeutic drug concentrations. These experimental findings demonstrated, for the first time, the applicability of HepaRG cells as a useful in vitro model for the prediction of metabolic-based drug-drug interactions, namely those mediated by metabolic induction. Thus, this model could potentially be a worthy alternative to the primary human hepatocytes. Topics: Amiodarone; Carcinoma, Hepatocellular; Cell Line, Tumor; Cytochrome P-450 Enzyme System; Drug Interactions; Enzyme Induction; Humans; Liver Neoplasms; Phenytoin; Rifampin | 2014 |
Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions.
Pruritus is a seriously disabling symptom accompanying many cholestatic liver disorders. Recent experimental evidence implicated the lysophospholipase, autotaxin (ATX), and its product, lysophosphatidic acid (LPA), as potential mediators of cholestatic pruritus. In this study, we highlight that increased serum ATX levels are specific for pruritus of cholestasis, but not pruritus of uremia, Hodgkin's disease, or atopic dermatitis. Treatment of patients with cholestasis with the bile salt sequestrant, colesevelam, but not placebo, effectively reduced total serum bile salts and fibroblast growth factor 19 levels, but only marginally altered pruritus intensity and ATX activity. Rifampicin (RMP) significantly reduced itch intensity and ATX activity in patients with pruritus not responding to bile salt sequestrants. In vitro, RMP inhibited ATX expression in human HepG2 hepatoma cells and hepatoma cells overexpressing the pregnane X receptor (PXR), but not in hepatoma cells in which PXR was knocked down. Treatment of severe, refractory pruritus by the molecular adsorbents recirculation system or nasobiliary drainage improved itch intensity, which, again, correlated with the reduction of ATX levels. Upon reoccurrence of pruritus, ATX activity returned to pretreatment values.. Serum ATX activity is specifically increased in patients with cholestatic, but not other forms of, systemic pruritus and closely correlates with the effectiveness of therapeutic interventions. The beneficial antipruritic action of RMP may be explained, at least partly, by the PXR-dependent transcriptional inhibition of ATX expression. Thus, ATX likely represents a novel therapeutic target for pruritus of cholestasis. Topics: Allylamine; Analysis of Variance; Antipruritics; Biomarkers; Blotting, Western; Carcinoma, Hepatocellular; Case-Control Studies; Cholestasis; Cohort Studies; Colesevelam Hydrochloride; Electrophoresis, Polyacrylamide Gel; Female; Fibroblast Growth Factors; Hep G2 Cells; Humans; Liver Neoplasms; Lysophospholipase; Male; Multivariate Analysis; Phosphoric Diester Hydrolases; Polymerase Chain Reaction; Pruritus; Rifampin; ROC Curve; Treatment Outcome | 2012 |
Management of rifamycins-everolimus drug-drug interactions in a liver-transplant patient with pulmonary tuberculosis.
Topics: Carcinoma, Hepatocellular; Cytochrome P-450 CYP3A; Drug Interactions; Enzyme Induction; Everolimus; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Rifabutin; Rifampin; Sirolimus; Tuberculosis, Pulmonary | 2012 |
Novel 1,2,3-triazole derivatives for use against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain.
The purpose of this study was to prepare various 4-substituted N-phenyl-1,2,3-triazole derivatives using click chemistry. The derivatives were screened in vitro for antimicrobial activity against Mycobacterium tuberculosis strain H37Rv (ATCC 27294) using the Alamar Blue susceptibility test. The activity was expressed as the minimum inhibitory concentration (MIC) in μg/mL (μM). Derivatives of isoniazid (INH), (E)-N'-[(1-aryl)-1H-1,2,3-triazole-4-yl)methylene] isonicotinoyl hydrazides, exhibited significant activity with MIC values ranging from 2.5 to 0.62 μg/mL. In addition, they displayed low cytotoxicity against liver cells (hepatoma HepG2) and kidney cells (BGM), thereby providing a high therapeutic index. The results demonstrated the potential and importance of developing new INH derivatives to treat mycobacterial infections. Topics: Antitubercular Agents; Carcinoma, Hepatocellular; Cell Proliferation; Click Chemistry; Humans; Isoniazid; Liver Neoplasms; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Triazoles; Tumor Cells, Cultured | 2011 |
Rifampicin as an oral angiogenesis inhibitor targeting hepatic cancers.
Angiogenesis is an important therapeutic target in cancer, and to fully exploit its therapeutic potential, combination chemotherapeutic/antiangiogenic regimens should be optimized and delivered earlier to more patients. Ideally, this could be done by a single potent oral agent with established safety. Rifampicin, a semisynthetic antibiotic derived from the rifamycins, is one of the most commonly used pharmaceutical compounds worldwide in the treatment of tuberculosis. Here, we present the effects of oral rifampicin on human cancer progression and its antiangiogenic properties, which were comparable to the angiogenesis inhibitor endostatin. Clinically, low-dose p.o. administration of rifampicin to six high-risk patients with hepatitis C virus-related liver cirrhosis resulted in a single occurrence of hepatocellular carcinoma during the follow-up period of 97.3 +/- 29.1 (mean +/- SD) months. Experimentally, rifampicin rapidly and markedly down-regulated the expression of a wide spectrum of angiogenesis-associated genes in growing human microvascular endothelial cells, thereby suppressing endothelial cell proliferation and migration. Rifampicin, at higher concentrations, also directly inhibited the growth of a variety of human cancer cells. P.o. administration of rifampicin significantly inhibited in vivo growth and metastases of subcutaneous human cancer xenografts. Thus, the potent antiangiogenic properties of oral rifampicin therapy were effective in suppressing cancer progression. It provides a promising new addition to antiangiogenic strategies for designing human cancer therapies. Considering the clinical pharmacokinetics of rifampicin, which enters the enterohepatic circulation and undergoes subsequent hepatic accumulation, it may be especially beneficial as an antitumor agent targeting hepatobiliary tumors. Topics: Administration, Oral; Aged; Angiogenesis Inhibitors; Animals; Carcinoma, Hepatocellular; Cells, Cultured; Drug Delivery Systems; Female; Follow-Up Studies; Hepatitis C; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Mice, Nude; Middle Aged; Rats; Rats, Wistar; Rifampin | 2009 |
Vitamin K2 suppresses proliferation and motility of hepatocellular carcinoma cells by activating steroid and xenobiotic receptor.
Vitamin K2, known as a cofactor for gamma-carboxylase, also serves as a ligand of a nuclear receptor, Steroid and Xenobiotic Receptor (SXR). Several clinical trials revealed that vitamin K2 reduced de novo formation and recurrence of hepatocellular carcinoma (HCC). To examine the role of SXR in HCC as a receptor activated by vitamin K2, the cells stably overexpressing SXR were established using a HCC cell line, HuH7. Overexpression of SXR resulted in reduced proliferation and motility of the cells. Further suppression of proliferation and motility was observed when SXR overexpressing clones were treated with vitamin K2. These results suggest that the activation of SXR could contribute to tumor suppressive effects of vitamin K2 on HCC cells. Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Hep G2 Cells; Humans; Liver Neoplasms; Pregnane X Receptor; Receptors, Steroid; Rifampin; Vitamin K 2 | 2009 |
Use of cryopreserved transiently transfected cells in high-throughput pregnane X receptor transactivation assay.
Cryopreserved, transiently transfected HepG2 cells were compared to freshly transfected HepG2 cells for use in a pregnane X receptor (PXR) transactivation assay. Assay performance was similar for both cell preparations; however, cryopreserved cells demonstrated less interassay variation. Validation with drugs of different PXR activation potencies and efficacies demonstrated an excellent correlation (r(2) > 0.95) between cryopreserved and fresh cells. Cryopreservation did not change the effect of known CYP3A4 inducers that have poor cell permeability, indicating that cryopreservation had little effect on membrane permeability. In addition, cryopreserved HepG2 cells did not exhibit enhanced susceptibility to cytotoxic compounds compared to transiently transfected control cells. The use of cryopreserved cells enables this assay to run with enhanced efficiency. Topics: Biological Assay; Caco-2 Cells; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Membrane Permeability; Cryopreservation; Drug-Related Side Effects and Adverse Reactions; Humans; Liver Neoplasms; Mifepristone; Pharmaceutical Preparations; Pregnane X Receptor; Receptors, Steroid; Reproducibility of Results; Rifampin; Sulfinpyrazone; Transcriptional Activation; Transfection | 2007 |
Pregnane X receptor activators inhibit human hepatic stellate cell transdifferentiation in vitro.
The activated pregnane X receptor is antifibrogenic in rodent chronic liver injury in vivo models. The aim of this study was to determine the effects of human pregnane X receptor activators on human hepatic stellate cell transdifferentiation to a profibrogenic phenotype in vitro.. Hepatic stellate cells were isolated from resected human liver and cultured under conditions in which they trans-differentiate into profibrogenic myofibroblasts.. The pregnane X receptor was expressed in primary cultures at the level of messenger RNA and protein and was activated by the ligand rifampicin as judged by increases in binding of proteins to the pregnane X receptor ER6 DNA response element and by increases in ER6-dependent reporter gene expression. Short-term treatment of hepatic stellate cells with rifampicin inhibited the expression of selected fibrosis-related genes (transforming growth factor beta1, alpha-smooth muscle actin), proliferation-related genes, and WNT signaling-associated genes. There was also an increase in interleukin-6 secretion and an inhibition in DNA synthesis. Long-term treatment with rifampicin over several weeks reduced the proliferation and transdifferentiation of hepatic stellate cells. Small interfering RNA knockdown of the pregnane X receptor in a hepatic stellate cell line reduced the binding of proteins to the ER6 DNA response element and abrogated pregnane X receptor activator-dependent changes in transforming growth factor beta1 expression, interleukin-6 secretion, and proliferation.. The pregnane X receptor is transcriptionally functional in human hepatic stellate cells and activators inhibit transdifferentiation and proliferation. The pregnane X receptor may therefore be an effective target for antifibrotic therapy. Topics: Blotting, Western; Carcinoma, Hepatocellular; Cell Differentiation; Cell Proliferation; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Hepatocytes; Humans; In Vitro Techniques; Liver Neoplasms; Pregnane X Receptor; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Reverse Transcriptase Polymerase Chain Reaction; Rifampin; RNA, Neoplasm; Tumor Cells, Cultured | 2006 |
Lignans, bacteriocides and organochlorine compounds activate the human pregnane X receptor (PXR).
The pregnane X receptor (PXR) mediates the induction of enzymes involved in steroid metabolism and xenobiotic detoxification. The receptor is expressed in liver and intestinal tissues and is activated by a wide range of compounds. The ability of a diverse range of dietary compounds to activate PXR-mediated transcription was assayed in HuH7 cells following transient transfection with human PXR (hPXR). The compounds investigated included phytochemicals such as lignans and phytoestrogens, organochlorine dietary contaminants such as polychlorinated biphenyls (PCBs) and triclosan and selected steroid, drug and herbal compounds. The hPXR activation at the top concentrations tested (10 microM) relative to the positive control 10 microM rifampicin ranged from 1.3% (trans-resveratrol) to 152% (ICI 182780). Hydroxylated compounds were marginally more potent than the parent compounds (tamoxifen activation was 74.6% whereas 4 hydroxytamoxifen activation was 84.2%) or significantly greater (vitamin D3 activation was 1.6%, while hydroxylated vitamin D3 activation was 55.6%). Enterolactone, the metabolite of common dietary lignans, was a medium activator of PXR (35.6%), compared to the lower activation of a parent lignan, secoisolariciresinol (20%). Two non-hydroxylated PCB congeners (PCB 118 and 153), which present a larger fraction of the PCB contamination of fatty foods, activated hPXR by 26.6% and 17%, respectively. The pesticide trans-nonachlor activation was 53.8%, while the widely used bacteriocide triclosan was a medium activator of hPXR at 46.2%. The responsiveness of PXR to activation by lignan metabolites suggests that dietary intake of these compounds may affect the metabolism of drugs that are CYP3A substrates. Additionally, the evidence that organochlorine chemicals, particularly the ubiquitous triclosan, activate hPXR suggests that these environmental chemicals may, in part, exhibit their endocrine disruptor activities by altering PXR-regulated steroid hormone metabolism with potential adverse health effects in exposed individuals. Topics: Alkaline Phosphatase; Anti-Bacterial Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Enzyme Inhibitors; Humans; Hydrocarbons, Chlorinated; Kinetics; Lignans; Liver Neoplasms; Phytoestrogens; Pregnane X Receptor; Quantitative Structure-Activity Relationship; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Retinoid X Receptors; Rifampin; Transfection | 2005 |
Human UDP-glucuronosyltransferase 1A5: identification, expression, and activity.
The human UDP-glucuronosyltransferase (UGT) subfamily 1A includes nine genes. The expression of all the UGT1A isoforms, apart from UGT1A5, has been reported previously. We have now detected a low basal level of UGT1A5 expression in cultured human hepatocytes, and treatment with rifampicin or 3-methylcholanthrene increased the level of UGT1A5 mRNA. Low-level UGT1A5 expression was also found in HepG2 and Caco-2 cells as well as human liver. Furthermore, UGT1A5 expression has been detected in various segments of the intestine from human donors, revealing high interindividual variability in its level and distribution along the intestine. Full-length UGT1A5 cDNA was isolated from Caco-2 cells that had been transfected with the pregnane X receptor and treated with rifampicin. Recombinant UGT1A5, expressed in baculovirus-infected insect cells, exhibited very low rates of 4-methylumbelliferone and scopoletin glucuronidation, whereas 1-hydroxypyrene was a much better substrate for it. UGT1A5 did not glucuronidate 4-aminobiphenyl, a good substrate for the highly homologous enzymes UGT1A4 and UGT1A3. However, replacing the first 110 amino acids of UGT1A5, a region that may be involved in substrate binding, with the counterpart segment from UGT1A4 did not increase the 4-aminobiphenyl glucuronidation activity. Collectively, this work demonstrates for the first time that the human UGT1A5 is expressed in several tissues, is inducible, and is catalytically active. Topics: Adult; Aged; Amino Acid Sequence; Animals; Baculoviridae; Caco-2 Cells; Carcinoma, Hepatocellular; Catalysis; Cell Line, Tumor; Cells, Cultured; DNA, Complementary; Gene Expression; Glucuronosyltransferase; Hepatocytes; Humans; Insecta; Intestinal Mucosa; Isoenzymes; Liver Neoplasms; Male; Methylcholanthrene; Middle Aged; Molecular Sequence Data; Recombinant Proteins; Rifampin; RNA, Messenger; Sequence Homology, Amino Acid; Substrate Specificity | 2005 |
A simultaneous assessment of CYP3A4 metabolism and induction in the DPX-2 cell line.
The DPX-2 cell line, a derivative of HepG2 cells, harbors human PXR and a luciferase-linked CYP3A4 promoter. These cells were used in a panel of cell-based assays for a parallel assessment of CYP3A4 induction, metabolism, and inhibition at the cellular level. CYP3A4 induction in the DPX-2 cell line by various agents was monitored in 96-well plates by a luciferase-based transcriptional activation assay. Of the prototypical CYP3A4 inducers examined, all exhibited elevated luciferase activity in DPX-2 cells. CYP3A4 enzyme activity in noninduced and rifampicin-induced DPX-2 cells was also assessed using Vivid fluorogenic substrates. Significantly elevated CYP3A4 activity levels (2.8-fold +/- 0.2-fold above DMSO-treated cells) were found in DPX-2 cells after 48 hours of exposure to rifampicin, but were undetectable in parental HepG2 cells. Rifampicin-induced activity levels were found to be suitable for assessing the inhibitory potential of new chemical entities in downstream CYP3A4 inhibition assays. The elevated CYP3A4 activity was inhibited 85% by 10 microM ketoconazole. In addition, a cytotoxicity assay to correct for possible toxic effects of compounds at the cellular level was applied. The comparative data obtained with a combination of the above assays suggests that the application of several independent in vitro technologies used in DPX-2 cells is the best possible strategy for the assessment of the complex phenomena of CYP3A4 induction and inhibition. Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Chromans; Clotrimazole; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dexamethasone; Dimethyl Sulfoxide; Enhancer Elements, Genetic; Enzyme Induction; Genes, Reporter; Genes, Synthetic; Humans; Ketoconazole; Liver Neoplasms; Lovastatin; Luciferases; Mifepristone; Neoplasm Proteins; Nifedipine; Omeprazole; Paclitaxel; Phenytoin; Pregnane X Receptor; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Recombinant Fusion Proteins; Rifampin; Thiazolidinediones; Transcription, Genetic; Troglitazone; Troleandomycin | 2005 |
CYP3A4 inducible model for in vitro analysis of human drug metabolism using a bioartificial liver.
CYP3A is responsible for approximately 50% of the therapeutic drug-metabolizing activity in the liver. The present study was undertaken to establish the CYP3A4 inducible model for analysis of human drug metabolism using a bioartificial liver composed of the functional hepatocellular carcinoma cell (HCC) line FLC-5. A radial-flow bioreactor (RFB), which is a carrier-filled type bioreactor, was used for 3-dimensional perfusion culture of FLC-5 cells. The CYP3A4 messenger RNA (mRNA) expression level 48 hours after rifampicin treatment in the RBF was approximately 100 times higher than that in a monolayer culture. Western blot analysis also demonstrated an increase in expression of the CYP3A protein. When testosterone, a substrate for CYP3A4, was added to the rifampicin-treated cell culture, 6 beta-hydroxy testosterone as a metabolite was formed. Electrophoretic mobility shift assay (EMSA) with a CYP3A4 ER6 probe demonstrated that relatively high molecular weight complex containing pregnane X receptor (PXR)/retinoid X receptor alpha(RXR alpha), compared with that in the monolayer culture, is possibly generated in the RFB culture of FLC-5 treated with rifampicin. Similarly, the assay with a probe of HNF-4 alpha-binding motif indicated the formation of a large protein complex in the RFB culture. Because it is known that PXR transactivates CYP3A4 gene via its response element and expression of PXR is regulated by HNF-4 alpha, the large complexes binding to response elements of PXR or HNF-4 alpha in the RFB culture may contribute to up-regulation of CYP3A4 mRNA. In conclusion, the bioartificial liver composed of human functional HCC cell line was useful in studying drug interactions during induction of human CYP3A4. Topics: Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Bioreactors; Carcinoma, Hepatocellular; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; DNA-Binding Proteins; Electrophoretic Mobility Shift Assay; Enzyme Induction; Gene Expression; Gene Expression Regulation; Hepatocyte Nuclear Factor 4; Humans; Liver; Liver Neoplasms; Microscopy, Electron; Microsomes, Liver; Models, Biological; Pharmaceutical Preparations; Phosphoproteins; Polymerase Chain Reaction; Pregnane X Receptor; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Rifampin; RNA, Messenger; Testosterone; Transcription Factors; Tumor Cells, Cultured | 2003 |
Relative receptor expression is a determinant in xenobiotic-mediated CYP3A induction in rat and human cells.
1. Species differences in xenobiotic-mediated transcriptional activation of CYP3A genes are known to exist. These differences are proposed to be due, in part, to host cell differences. 2. Host cell effects were investigated by trans-species transient transfection of reporter genes containing either the rat CYP3A23 or human CYP3A4 proximal promoters into human HepG2 and rat FaO and H4IIEC3 hepatoma cells. HepG2 and FaO cells supported activation of both CYP3A constructs by xenobiotics in a species-specific manner, whereas H4IIEC3 cells were non-permissive. 3. The mRNA complement of the cell lines was then quantified by semiquantitative RT-PCR for adult CYP3As (CYP3A23, CYP3A4/5), steroid hormone receptors (constitutive androstane receptor, glucocorticoid receptor-alpha, pregnane X receptor) and transcription factors (Hepatic nuclear factor 4alpha, retinoid X receptor). 4. Principal component analysis of absolute receptor levels demonstrated a wide scattering, with no coherent pattern. In contrast, PCA of relative receptor ratios segregated H4IIEC3 cells from all other samples. 5. The observation is confirmed that species differences in response to xenobiotics are a result of host cell environment. In addition, new evidence is provided to support the hypothesis that in addition to individual receptor activation profiles, the relative abundance of steroid hormone receptors that control CYP3A gene expression play an important role in this observed species difference. Topics: Animals; Aryl Hydrocarbon Hydroxylases; Carcinoma, Hepatocellular; Cell Line, Tumor; Cytochrome P-450 CYP3A; Dexamethasone; Dose-Response Relationship, Drug; Gene Expression Profiling; Gene Expression Regulation, Enzymologic; Humans; Liver Neoplasms; Oxidoreductases, N-Demethylating; Pregnane X Receptor; Rats; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Rifampin; Species Specificity; Tissue Distribution; Transcription Factors | 2003 |
A reporter gene assay to assess the molecular mechanisms of xenobiotic-dependent induction of the human CYP3A4 gene in vitro.
1. A plasmid containing 1 kb of the CYP3A4 regulatory (promoter) region coupled to a reporter gene for secretary placental alkaline phosphatase (SPAP) was transfected into HepG2 cells. Transfected cells were dosed with several known inducers of CYP3A4 and the levels of SPAP were measured. The effect of co-transfecting a plasmid encoding the human glucocorticoid receptor on reporter gene activity was also examined. 2. Dexamethasone induced CYP3A4-dependent reporter gene expression in a concentration-dependent manner and induction was approximately doubled in the presence of the glucocorticoid receptor. Dexamethasone-dependent induction was blocked by RU-486 (a glucocorticoid receptor antagonist), in the presence of the co-transfected glucocorticoid receptor. 3. Induction of CYP3A4-dependent reporter gene expression and enhancement of the induction by the glucocorticoid receptor was also observed with pregnenolone-16alpha-carbonitrile (PCN), rifampicin, phenytoin, carbamazepine, phenylbutazone and phenobarbitone, all known in vivo inducers of CYP3A4 in man. 4. Metyrapone and sulfinpyrazone induced CYP3A4-dependent reporter gene expression, but induction was not enhanced by the glucocorticoid receptor. 5. Clotrimazole, erythromycin and triacetyloleandomycin (TAO) did not induce CYP3A4-dependent reporter gene expression, consistent with the observation that these inducers act through post-transcriptional mechanisms. 6. These results highlight differences in the molecular mechanisms of induction of CYP3A4 by the xenobiotics studied and indicate that the glucocorticoid receptor is involved in the induction of the CYP3A4 gene by some, but not all, CYP3A4 inducers. 7. We propose that the approach described here provides a useful in vitro approach for the identification of transcriptional regulators of the CYP3A4 gene. Topics: Alkaline Phosphatase; beta-Naphthoflavone; Caffeine; Carbamazepine; Carcinoma, Hepatocellular; Clofibrate; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Dexamethasone; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Gene Expression Regulation; Genes, Reporter; Glucocorticoids; Hormone Antagonists; Humans; Isoniazid; Mifepristone; Mixed Function Oxygenases; Phenobarbital; Phenylbutazone; Phenytoin; Receptors, Glucocorticoid; Recombinant Proteins; Rifampin; Tumor Cells, Cultured; Xenobiotics | 1999 |
Rifampicin and isoniazid increase acetaminophen and isoniazid cytotoxicity in human HepG2 hepatoma cells.
Acetaminophen (APAP) induced a concentration-dependent (0-30 mM) cytotoxic effect in human HepG2 hepatoma cells which was significantly increased when intracellular reduced glutathione (GSH) content was decreased. The cytotoxic effect of APAP (0-30 mM) was significantly lower in a day 3-treated compared to day 1-treated HepG2 cells. A 3-day preincubation of HepG2 cells with 5 microM 3-methylcholanthrene (3MC), 50 microM rifampicin (RFP) or 1 mM isoniazid (INH) significantly increased 15-30 mM APAP cytotoxicity, of about 15-20% for INH and RFP and 35-50% for 3MC. The cytotoxicity of 10 mM APAP was also increased (about 20%) by a 3-day preincubation with INH but was not affected by 3MC and RFP. INH induced a concentration-dependent (0-40 mM) cytotoxic effect in day-1 treated HepG2 cells and not significantly affected by decreases in intracellular GSH concentrations. INH was not cytotoxic in day 3-treated HepG2 cells. A 3-day preincubation of HepG2 cells with 50 mM RFP or 1 mM INH significantly increased 10-40 mM INH cytotoxicity, respectively of about 10% and 10-25%. A 3-day preincubation with 3MC did not modify the cytotoxic effect of INH at these concentrations. This is to our knowledge the first report of increases by INH and RFP of APAP of INH cytotoxicity in vitro in hepatocellular cells of human origin. It is in accordance with clinical observations of severe hepatotoxicity associated with APAP or INH usage in patients receiving multiple drug therapy (INH, RFP) for tuberculosis or in alcoholics. Topics: Acetaminophen; Analgesics, Non-Narcotic; Antitubercular Agents; Carcinoma, Hepatocellular; Cell Survival; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Interactions; Glutathione; Humans; Isoniazid; Liver Neoplasms; Methylcholanthrene; Rifampin; Tumor Cells, Cultured | 1997 |
Expression and inducibility of UDP-glucuronosyltransferases 1-naphthol in human cultured hepatocytes and hepatocarcinoma cell lines.
The UDP-glucuronosyltransferase (UGTs) isoforms involved in the conjugation of 1-naphthol were characterized in human cultured hepatocytes and in two human hepatocarcinoma cell lines, KYN-2 and Mz-Hep-1 in terms of expression, kinetics and induction by drugs. Their properties were compared to those of UGT1*6 stably expressed in the V79 cell line (V79UGT1*6), which glucuronidates 1-naphthol preferentially. The determination of kinetic constants for glucuronidation of 1-naphthol revealed a two-site model in human hepatocytes, but a one-site model in the two hepatocarcinoma cell lines. Southern blot analysis of RT-PCR products, showed that the UGT1*6 mRNA was expressed in KYN-2, but not in Mz-Hep-1 cells. However, a mRNA encoding a UGT different from UGT1*6 was expressed in Mz-Hep-1 cells. The two inducers, beta-naphthoflavone and rifampicin exerted a differential effect, depending on the cell lines considered. Altogether, the results suggest that, in hepatocytes, two UGT isoforms, which glucuronidate 1-naphthol are expressed and are differentialy regulated by inducers. Both KYN-2 and Mz-Hep-1 cells express one of the two different UGT isoforms found in hepatocytes. The UGT isoform present in KYN-2 cells corresponds to UGT1*6, whereas in Mz-Hep-1 cells the UGT isoform present was different from UGT1*6 and UGT1*7. Topics: beta-Naphthoflavone; Carcinoma, Hepatocellular; Cell Line; Enzyme Induction; Gene Expression Regulation, Enzymologic; Glucuronates; Glucuronosyltransferase; Humans; Liver; Liver Neoplasms; Naphthols; Rifampin; Tumor Cells, Cultured | 1997 |
Inducibility of ethoxyresorufin deethylase and UDP-glucuronosyltransferase activities in two human hepatocarcinoma cell lines KYN-2 and Mz-Hep-1.
Two human hepatoma cell lines, KYN-2 and Mz-Hep-1 were characterized in terms of glucuronidation capacity and inducibility of cytochrome P4501A1/1A2 and several UDP-glucuronosyltransferases (UGTs). Cytochrome P4501A1/1A2 activity was measured using 7-ethoxyresorufin and that of UGTs with 16 different substrates. The effects of dimethyl sulfoxide (DMSO), 3-naphthoflavone, alpha-naphthoflavone, and rifampicin on these drug-metabolizing enzyme activities were studied. DMSO treatment increased in a dose-dependent manner the ethoxyresorufin O-deethylase (EROD) activity in KYN-2 cells, while an opposite effect was observed in Mz-Hep-1 cells. In KYN-2 cells, EROD was more responsive toward beta-naphthoflavone treatment in combination with DMSO. This activity was enhanced in Mz-Hep-1 cells more than 83 times by beta-naphthoflavone. The enhancement of EROD activity by DMSO and beta-naphthoflavone treatments of KYN-2 cells was abolished by alpha-naphthoflavone treatment. In Mz-Hep-1, only the inducing effect of beta-naphthoflavone was abolished by alpha-naphthoflavone treatment. Rifampicin treatment of KYN-2 cells reversed both the DMSO and beta-naphthoflavone effects on the EROD activity. Glucuronidation of steroids, bile acids, fatty acids and drugs was effective in KYN-2 and Mz-Hep-1 cells. Both 1-naphthol glucuronidation and the level of UGT1*6 protein detected by immunoblot and supporting this activity were lowered by DMSO treatment and increased by beta-naphthoflavone treatment in KYN-2 cells. In Mz-Hep-1 cells, DMSO and beta-naphthoflavone had no effect on 1-naphthol glucuronidation activity. DMSO, beta-naphthoflavone and rifampicin also affected the glucuronidation of various substrates supported by different UGT isoforms. These results indicate that KYN-2 and Mz-Hep-1 cells can be used as new in vitro models for the studies of drug metabolism and the regulation of the corresponding enzymes. Topics: Antibiotics, Antitubercular; Benzoflavones; beta-Naphthoflavone; Carcinoma, Hepatocellular; Cytochrome P-450 CYP1A1; Cytochrome P-450 Enzyme System; Dimethyl Sulfoxide; Enzyme Activation; Enzyme Induction; Glucuronosyltransferase; Humans; Isomerism; Oxidoreductases; Rifampin; Substrate Specificity; Tumor Cells, Cultured; Uridine Diphosphate | 1996 |
The effects of inducing agents on cytochrome P450 and UDP-glucuronyltransferase activities in human HEPG2 hepatoma cells.
Selective induction in vitro of cytochrome P450-dependent mixed-function oxidase (MFO) and UDP-glucuronyltransferase (GT) activities was observed in the human HepG2 hepatoma cell line. 1,2-Benzanthracene (BA) induced MFO O-dealkylation activities for ethoxyresorufin, methoxyresorufin and benzyloxyresorufin, whereas phenobarbitone (PB) selectively induced pentoxyresorufin O-dealkylation and rifampicin (RIF) selectively induced benzyloxyresorufin O-dealkylation. Antibody inhibition experiments indicated that ethoxyresorufin and methoxyresorufin O-dealkylations were catalysed mainly by the P450 1A subfamily in untreated and BA-induced HepG2 cells, that additional unidentified P450 forms were considerably involved in methoxyresorufin and benzyloxyresorufin O-dealkylations and that the P450 2B subfamily was partially responsible for pentoxyresorufin O-dealkylation in PB-induced cells. Bilirubin GT activity was induced by PB, BA, RIF and dexamethasone, but 1-naphthol, morphine and testosterone GT activities were not induced by any of these treatments. Topics: Benz(a)Anthracenes; Carcinoma, Hepatocellular; Cytochrome P-450 Enzyme System; Dexamethasone; Enzyme Induction; Glucuronosyltransferase; Humans; Mixed Function Oxygenases; Phenobarbital; Rifampin; Tumor Cells, Cultured | 1993 |
Post-transcriptional inhibition of protein synthesis by rifampicin in rat hepatoma cells.
Topics: Ammonium Sulfate; Animals; Carbon Isotopes; Carcinoma, Hepatocellular; Cell Line; Cell Nucleus; DNA-Directed RNA Polymerases; Enzyme Activation; Enzyme Induction; Hydrocortisone; Leucine; Liver Neoplasms; Magnesium; Manganese; Neoplasm Proteins; Protein Biosynthesis; Rats; Rifampin; RNA, Neoplasm; Transcription, Genetic; Tyrosine Transaminase; Uracil | 1973 |
Effect of various anticancer agents on DNA polymerase.
Topics: Adenosine Triphosphate; Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Bleomycin; Bone Marrow; Carcinoma, Hepatocellular; Cytosine Nucleotides; Dactinomycin; Deoxyribonucleotides; DNA Nucleotidyltransferases; DNA, Neoplasm; Fluorouracil; Guanosine Triphosphate; Liver; Liver Neoplasms; Liver Regeneration; Mitomycins; Neoplasms, Experimental; Rats; Rifampin; Thymidine; Tritium | 1971 |