Abstract:
:The current test systems employed by pharmaceutical industry are poorly predictive for drug-induced liver injury (DILI). The 'MIP-DILI' project addresses this situation by the development of innovative preclinical test systems which are both mechanism-based and of physiological, pharmacological and pathological relevance to DILI in humans. An iterative, tiered approach with respect to test compounds, test systems, bioanalysis and systems analysis is adopted to evaluate existing models and develop new models that can provide validated test systems with respect to the prediction of specific forms of DILI and further elucidation of mechanisms. An essential component of this effort is the choice of compound training set that will be used to inform refinement and/or development of new model systems that allow prediction based on knowledge of mechanisms, in a tiered fashion. In this review, we focus on the selection of MIP-DILI training compounds for mechanism-based evaluation of non-clinical prediction of DILI. The selected compounds address both hepatocellular and cholestatic DILI patterns in man, covering a broad range of pharmacologies and chemistries, and taking into account available data on potential DILI mechanisms (e.g. mitochondrial injury, reactive metabolites, biliary transport inhibition, and immune responses). Known mechanisms by which these compounds are believed to cause liver injury have been described, where many if not all drugs in this review appear to exhibit multiple toxicological mechanisms. Thus, the training compounds selection offered a valuable tool to profile DILI mechanisms and to interrogate existing and novel in vitro systems for the prediction of human DILI.
journal_name
Arch Toxicoljournal_title
Archives of toxicologyauthors
Dragovic S,Vermeulen NP,Gerets HH,Hewitt PG,Ingelman-Sundberg M,Park BK,Juhila S,Snoeys J,Weaver RJdoi
10.1007/s00204-016-1845-1subject
Has Abstractpub_date
2016-12-01 00:00:00pages
2979-3003issue
12eissn
0340-5761issn
1432-0738pii
10.1007/s00204-016-1845-1journal_volume
90pub_type
杂志文章,评审abstract::Whether pregnancy-induced immunosuppression when combined with exposure to 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) could exacerbate immunotoxicity has not been previously investigated. The current study evaluated the immune status of C57BL/6 pregnant and virgin mice following exposure to TCDD. To this end, syngene...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-003-0538-8
更新日期:2004-05-01 00:00:00
abstract::Fifteen patients who were severely poisoned with either hypnotic drugs or salicylate were treated by charcoal haemoperfusion. The device contained 100g of activated charcoal immobilised by fixation to a polyester film. Two patients showed no response and eventually died. The remainder showed marked lightening of coma ...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF01270911
更新日期:1980-07-01 00:00:00
abstract::Treatment of cats with acrylamide, either 7.5 or 15 mg/kg IM, once a day for 10 days, resulted in increases of 31 and 47% in the phospholipid content of sciatic nerve, respectively, from a control level of 41.1 +/- 2.7 mg/kg wet weight. Determination of the distribution of individual phospholipids indicated no signifi...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF00316124
更新日期:1984-09-01 00:00:00
abstract::The aryl hydrocarbon receptor (AHR) is known to mediate the cellular response to numerous xenobiotics including dioxin. Surprisingly AHR knockout mice provide evidence for the involvement of the AHR signalling cascade in estrogen regulated physiological functions of the female reproductive system. Several studies alre...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-012-0870-y
更新日期:2012-10-01 00:00:00
abstract::Sexual differentiation in the brain takes place from late gestation to the early postnatal days. This is dependent on the conversion of circulating testosterone into estradiol by the enzyme aromatase. The glyphosate was shown to alter aromatase activity and decrease serum testosterone concentrations. Thus, the aim of ...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-011-0788-9
更新日期:2012-04-01 00:00:00
abstract::Conventional in vitro toxicity studies have focused on identifying IC50 and the underlying mechanisms, but how toxicants influence biophysical and biomechanical changes in human cells, especially during developmental stages, remain understudied. Here, using an atomic force microscope, we characterized changes in bioph...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-019-02549-9
更新日期:2019-10-01 00:00:00
abstract::Environmental carcinogens-induced lung cancer and potential mechanisms have attracted widespread attention. Currently, microRNAs (miRNAs) have been recognized as key players in development of cancer, among which guide strand of miRNA has been well documented rather than its passenger strand (miRNA*). Our previous stud...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-015-1551-4
更新日期:2016-05-01 00:00:00
abstract::Nephrotoxicity is a major side effect of cisplatin in chemotherapy. Pathologically, cisplatin nephrotoxicity is characterized by cell injury and death in renal tubules. The research in the past decade has gained significant understanding of the cellular and molecular mechanisms of tubular cell death, revealing a centr...
journal_title:Archives of toxicology
pub_type: 杂志文章,评审
doi:10.1007/s00204-014-1239-1
更新日期:2014-06-01 00:00:00
abstract::Hydroxysteroid sulfotransferase 2B1b (SULT2B1b) sulfates cholesterol and oxysterols. Hepatic oval cells (HOCs), thought to be progenitor cells, can be triggered in chemically injured livers. The present study focused on the role of SULT2B1b in HOC proliferation after liver injury. Our experiments revealed that the exp...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-016-1693-z
更新日期:2017-01-01 00:00:00
abstract::Human precision-cut liver slices (hPCLS) are a valuable ex vivo model that can be used in acute toxicity studies. However, a rapid decline in metabolic enzyme activity limits their use in studies that require a prolonged xenobiotic exposure. The aim of the study was to extend the viability and function of hPCLS to 5 d...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-016-1865-x
更新日期:2017-05-01 00:00:00
abstract::The goal of these studies was to characterize the role played by antigen challenge in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced immunosuppression. The effects of single exposure to TCDD (4.2, 14, and 42 microg/kg) in B6C3F1 mice on the reverse plaque assay (RPA; no sensitization) and the sheep red blood cell ...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s002040050467
更新日期:1997-01-01 00:00:00
abstract::Sertoli cells play a critical role in spermatogenesis, and in adults, they are terminally differentiated with loss of proliferative activity. This study revealed Sertoli cell proliferation in 17-week-old Sprague-Dawley rats whose dams had been intragastrically administered 250 ng of 3,3',4,4',5-pentachlorobiphenyl/kg ...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-011-0736-8
更新日期:2012-01-01 00:00:00
abstract::The effect of culture medium on glutathione (GSH) dependent detoxification defence system of primary cultured hepatocyte from either male or female rats was studied. Intracellular reduced (GSH) and oxidized glutathione (GSSG), and six GSH-related enzyme activities, including GSH peroxidase (GSH Px), GSH reductase (GSH...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s002040050345
更新日期:1996-01-01 00:00:00
abstract::Arsenic-containing hydrocarbons (AsHCs), a subgroup of arsenolipids found in fish and algae, elicit substantial toxic effects in various human cell lines and have a considerable impact on cellular energy levels. The underlying mode of action, however, is still unknown. The present study analyzes the effects of two AsH...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-018-2194-z
更新日期:2018-05-01 00:00:00
abstract::The aim of this study was to assess the neurotoxicity of diazinon oxon (DZO), a major in vivo metabolite of the phosphorothionate insecticide diazinon (DZ), on differentiating mouse N2a neuroblastoma cells. When used at concentrations of 1, 5 and 10 microM, DZO did not cause cell death but it impaired the outgrowth of...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-008-0339-1
更新日期:2009-04-01 00:00:00
abstract::Rhabdomyolysis has been reported in patients who abuse synthetic cannabinoids. However, no studies have yet assessed whether these cases reflect the direct cytotoxicity of synthetic cannabinoids on skeletal muscle, a possibility that the present study sought to address. Specifically, this study investigated the cytoto...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-020-02944-7
更新日期:2020-11-10 00:00:00
abstract::Neurotoxic properties of acrylamide and seven related compounds in rats were studied with regard to the effects on rotarod performance, morphology of nerves and neurotubulin. Compounds used in the present study were acrylamide, N-hydroxymethylacrylamide, N-isopropylacrylamide, methacrylamide, N-methylacrylamide, croto...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF01239204
更新日期:1983-11-01 00:00:00
abstract::A study was conducted to determine the levels of cis-diamminedichloroplatinum (II) (cisplatin) in plasma proteins and hemoglobin of cancer patients after cisplatin chemotherapy. Thirty-seven cancer patients with different type of cancers (lung, esophageal, urinary tract, and testicular cancer, melanoma, osteosarcoma e...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF00303124
更新日期:1989-01-01 00:00:00
abstract::Sulfur dioxide (SO2) is a common air pollutant, and inhaled SO2 in airway epithelium easily forms its soluble derivatives in vivo (bisulfite and sulfite), which are toxic to the respiratory system and related to the exacerbation of asthma. To investigate the effects of SO2 derivatives on the expressions of asthma rela...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-007-0212-7
更新日期:2007-12-01 00:00:00
abstract::The object of this study was to compare the relative sensitivity of markers of exposure and effects in the lung of rats exposed to polymeric diphenyl-methane-4,4'-diisocyanate (pMDI) aerosol. Rats were repeatedly exposed to 12.9 mg pMDI/m(3) (6 h/day, 5 days/week for 14 days; exposure was from days 0--17 followed by a...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-001-0301-y
更新日期:2002-02-01 00:00:00
abstract::Recently, acutely toxic doses of the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have been reported to affect the hepatic distribution of essential metals in the rat. However, the reduced food intake by TCDD was not taken into account. Therefore, metal concentrations were determined in different...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF02284268
更新日期:1991-01-01 00:00:00
abstract::Although polybrominated naphthalenes (PBNs) are contaminants of the commercial fire retardant fireMaster BP-6, the individual PBN isomers have not been identified. In order to study PBNs possessing an analogous level of bromination to those found in fireMaster BP-6, three synthetic PBN mixtures, averaging 5.0, 5.3, an...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF00346051
更新日期:1984-07-01 00:00:00
abstract::The present study was carried out to elucidate the mechanisms behind an increase in the incidence of malignant or multiple mammary tumors as a result of oral administration of rolipram in a 104-week carcinogenicity study. The organs and tissues of Sprague-Dawley (SD) rats of both sexes, which had been subjected to a 1...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-005-0016-6
更新日期:2006-02-01 00:00:00
abstract::The neurological effects of four synthetic pyrethroids resmethrin, permethrin, cypermethrin, and deltamethrin have been investigated in the rat to establish whether there is a correlation between the clinical-functional status of the animal and peripheral nerve damage as measured biochemically. Neuromuscular dysfuncti...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF00294995
更新日期:1983-08-01 00:00:00
abstract::Rodents are relatively insensitive to the neurotoxic effects of various organophosphorus compounds. The purpose of this investigation was to determine if differences in inactivation of CBDP could explain the strain differences in the sensitivity to neurotoxicity following administration of TOCP (tri-o-cresyl phosphate...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF01973466
更新日期:1990-01-01 00:00:00
abstract::During aerobic incubation of trichloroethylene with rabbit liver microsomes and NADPH a difference absorption peak appears at 451-452 nm. Trichloroethylene does not form a ligand absorption spectrum with hepatic microsomes reduced by dithionite, or in anaerobic incubates in the presence of NADPH. Addition of trichloro...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF00293858
更新日期:1977-06-18 00:00:00
abstract::A single dose of 10 mg methylmercury chloride per kg body weight was given to 30 days old rats and to adult rats (180-200g)(. This resulted in brain levels of 1.4-2.2 micrograms Hg/g wet weight. In the young rats electron microscopic morphometry showed swelling of the granule cells. The extent of changes was more pron...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF00332352
更新日期:1981-04-01 00:00:00
abstract::The effect of acute and chronic cadmium administration on hepatic drug metabolism was investigated in the male rat. 3 days after the acute administration of cadmium by either the intraperitoneal (0.84 mg Cd/kg) or the oral (greater than 80 mg Cd/kg) route, there was a significant potentiation in duration of hexobarbit...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF00310332
更新日期:1978-08-09 00:00:00
abstract::Between 0.25-25 micrograms of an aqueous solution of either mercuric chloride or methyl mercuric acetate was injected directly into the sciatic nerve of 28 adult Wistar rats. The resultant pathological changes in the nerve were examined by teasing individual fibres and by light and electron microscopy. In most respect...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/BF00310442
更新日期:1980-12-01 00:00:00
abstract::MicroRNAs (miRNAs) are a family of endogenous, small, noncoding RNA molecules that involved in a wide range of biological processes including differentiation, proliferation, and apoptosis. A polymorphism G>C (rs2910164) is located in the stem region opposite to the mature miR-146a sequence. In our study, we investigat...
journal_title:Archives of toxicology
pub_type: 杂志文章
doi:10.1007/s00204-012-1004-2
更新日期:2013-05-01 00:00:00