Development of Prediction Models for Drug-Induced Cholestasis, Cirrhosis, Hepatitis, and Steatosis Based on Drug and Drug Metabolite Structures

In this study, we developed binary classification models to predict drug-induced cholestasis, cirrhosis, hepatitis, and steatosis based on the structure of drugs and their metabolites. DILI-positive data was obtained from post-market reports of drugs and DILI-negative data from DILIrank, a database curated by the Food and Drug Administration (FDA). Support vector machine (SVM) and random forest (RF) were used in developing models with nine fingerprints and one 2D molecular descriptor calculated from drug (152 DILI-positives and 102 DILI-negatives) and drug metabolite (192 DILI-positives and 126 DILI-negatives) structures. Models were developed according to Organisation for Economic Co-operation and Development (OECD) guidelines for quantitative structure-activity relationship (QSAR) validation. Internal and external validation was performed with a randomization test in order to thoroughly examine model predictability and avoid random correlation between structural features and adverse outcomes. The applicability domain was defined with a leverage method for reliable prediction of new chemicals. The best models for each liver disease were selected based on external validation results from drugs (cholestasis: 70%, cirrhosis: 90%, hepatitis: 83%, and steatosis: 85%) and drug metabolites (cholestasis: 86%, cirrhosis: 88%, hepatitis: 86%, and steatosis: 83%) with applicability domain analysis. Compiled data sets were further exploited to derive privileged substructures that were m...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research

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AbstractA complex relationship exists between thyroid and liver in health and disease. Liver plays an essential physiological role in thyroid hormone activation and inactivation, transport, and metabolism. Conversely, thyroid hormones affect activities of hepatocytes and hepatic metabolism. Serum liver enzyme abnormalities observed in hypothyroidism may be related to impaired lipid metabolism, hepatic steatosis or hypothyroidism-induced myopathy. Severe hypothyroidism may have biochemical and clinical features, such as hyperammonemia and ascites, mimicking those of liver failure. Liver function tests are frequently abnorma...
Source: Journal of Endocrinological Investigation - Category: Endocrinology Source Type: research
Conclusions: Fibroscan is an accurate non-invasive method for the diagnosis of fibrosis in alcoholic patients. TE values below 11 and 30 kPa likely rule out significant fibrosis and varices, respectively.
Source: Journal of Clinical Gastroenterology - Category: Gastroenterology Tags: LIVER, PANCREAS & BILIARY TRACT: Original Articles Source Type: research
Discussion The liver is one of the largest organs in the body, weighing just over 3 pounds in an adult. It is found in the upper right abdomen, under the right dome of the diaphragm. Grossly, it has asymmetric lobes with the right being larger than the left. The lobes are separated by a fibrous connective tissue band that also anchors the liver in the abdominal cavity. The gallbladder is located on the inferior surface of the liver and stores bile, which is then released into the duodenum. Microscopically, the liver cells are arranged in lobules with canals carrying blood vessels and bile ducts. At any moment about 10-13% ...
Source: PediatricEducation.org - Category: Pediatrics Authors: Tags: Uncategorized Source Type: news
Abstract OBJECTIVES: Liver transplant has been used as a curative approach for children with end-stage liver diseases. Here, we describe the underlying causes for pediatric liver transplant performed at the Shiraz Organ Transplantation Center, Nemazee Hospital, Shiraz, Iran. MATERIALS AND METHODS: In this cross-sectional des-criptive study, children
Source: Experimental and Clinical Transplantation : official journal of the Middle East Society for Organ Transplantation - Category: Transplant Surgery Authors: Tags: Exp Clin Transplant Source Type: research
Nutritional deficiencies have become a common problem among patients with chronic liver disease (CLD) and may easily be underestimated by clinical appearance alone; they negatively impact the neurocognitive development and growth. CLD is defined as the process of long-term progressive destruction and regeneration of liver parenchyma leading to fibrosis and cirrhosis. Children with CLD are more at risk than adults for severe malnutrition and feature lower reserves. In the United States, the overall incidence of liver disease in neonates is approximately 1 in every 2500 live births1 with extrahepatic biliary atresia (BA), me...
Source: Pediatrics and Neonatology - Category: Perinatology & Neonatology Authors: Tags: Editorial Source Type: research
Excessive alcohol consumption can lead to a spectrum of liver histopathology, including steatosis, steatohepatitis, foamy degeneration, fatty liver with cholestasis, and cirrhosis. Although variability in sampling and pathologist interpretation are of some concern, liver biopsy remains the gold standard for distinguishing between steatohepatitis and noninflammatory histologic patterns of injury that can also cause the clinical syndrome of alcohol-related hepatitis. Liver biopsy is not routinely recommended to ascertain a diagnosis of alcohol-related liver disease in patients with an uncertain alcohol history, because the h...
Source: Clinics in Liver Disease - Category: Gastroenterology Authors: Source Type: research
Abstract Pediatric hepatocellular carcinoma (HCC) is the second common malignant liver tumor in children after hepatoblastoma. It differs from the adult HCC in the etiological predisposition, biological behavior and lower frequency of cirrhosis. Perinatally acquired hepatitis-B virus, hepatorenal tyrosinemia, progressive familial intrahepatic cholestasis, glycogen storage disease, Alagille's syndrome and congenital portosystemic shunts are important predisposing factors. Majority of children (87%) are older than 5 years of age. Following mass immunization against hepatitis-B, there has been a drastic fall in the i...
Source: World Journal of Gastroenterology : WJG - Category: Gastroenterology Authors: Tags: World J Gastroenterol Source Type: research
Publication date: Available online 28 May 2018Source: Arab Journal of GastroenterologyAuthor(s): Devaraj EzhilarasanAbstractOxidative stress plays an important role in the pathogenesis of various chronic liver diseases (CLD) and increasing evidence have confirmed the contributory role of oxidative stress in the pathogenesis of drugs and chemical-induced CLD. Chronic liver injury is manifested as necrosis, cholestasis, fibrosis, and cirrhosis. Chronic administration of anti-tubercular, anti-retroviral, immunosuppressive drugs is reported to induce free radical generation during their biotransformation in the liver. Further,...
Source: Arab Journal of Gastroenterology - Category: Gastroenterology Source Type: research
Conclusion Children with classical AATD commonly have chronic liver disease. In heterozygous (PiMZ) children with AATD, enzyme levels can normalize with occasional fluctuations, sometimes causing delayed diagnosis.
Source: European Journal of Gastroenterology and Hepatology - Category: Gastroenterology Tags: Original Articles: Hepatology Source Type: research
Publication date: Available online 28 May 2018 Source:Arab Journal of Gastroenterology Author(s): Devaraj Ezhilarasan Oxidative stress plays an important role in the pathogenesis of various chronic liver diseases (CLD) and increasing evidence have confirmed the contributory role of oxidative stress in the pathogenesis of drugs and chemical-induced CLD. Chronic liver injury is manifested as necrosis, cholestasis, fibrosis, and cirrhosis. Chronic administration of anti-tubercular, anti-retroviral, immunosuppressive drugs is reported to induce free radical generation during their biotransformation in the liver. Further, thes...
Source: Arab Journal of Gastroenterology - Category: Gastroenterology Source Type: research
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