Abstract：
:We report here the results of a collaborative research program to develop a robust and reliable in vitro system to allow an accurate definition of the drug-induced liver injury (DILI) potential of new drug entities during drug development. The in vitro hepatotoxic potential of 152 drugs with known DILI profiles were evaluated in primary cultured human hepatocytes with four mechanistically-relevant endpoints: cellular ATP depletion, reactive oxygen species (ROS), glutathione (GSH) depletion, and caspase activation for apoptosis. The drugs, 80 in the testing set and 72 in the validation set, were classified based on serious clinical/regulatory outcomes as defined by reported acute liver failure, black-box warning, and/or withdrawal. The drugs were further sub-categorized for dominant types of liver injury. Logistic regression models were performed to calculate the area under the receiver operating characteristics curve (AUROC) and to evaluate the prediction potential of the selected endpoints for serious clinical/regulatory outcomes. The ROS/ATP ratio was found to yield an excellent AUROC in both the testing (0.8989, P < 0.0001) and validation set (0.8545, P < 0.0001), and was found to distinguish drugs associated with severe from non-severe DILI cases (p < 0.0001). The results suggest that evaluation of drugs in primary human hepatocytes using the ROS/ATP ratio endpoint may aid the definition of their potential to cause severe DILI.
journal_name
Chem Biol Interactjournal_title
Chemico-biological interactionsauthors
Zhang J,Doshi U,Suzuki A,Chang CW,Borlak J,Li AP,Tong Wdoi
10.1016/j.cbi.2015.11.008subject
Has Abstractpub_date
2016-08-05 00:00:00pages
3-11eissn
0009-2797issn
1872-7786pii
S0009-2797(15)30110-1journal_volume
255pub_type
杂志文章abstract：:Oxalate induced renal calculi formation and the associated renal injury is thought to be caused by free radical mediated mechanisms. An in vivo model was used to investigate the effect of phycocyanin (from Spirulina platensis), a known antioxidant, against calcium oxalate urolithiasis. Male Wistar rats were divided in...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2004.05.006
更新日期：2004-08-10 00:00:00
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journal_title：Chemico-biological interactions
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journal_title：Chemico-biological interactions
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journal_title：Chemico-biological interactions
pub_type： 杂志文章,评审
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journal_title：Chemico-biological interactions
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doi：10.1016/j.cbi.2015.10.013
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journal_title：Chemico-biological interactions
pub_type： 杂志文章
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journal_title：Chemico-biological interactions
pub_type： 杂志文章
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journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2011.01.031
更新日期：2011-05-30 00:00:00
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journal_title：Chemico-biological interactions
pub_type： 杂志文章,评审
doi：10.1016/0009-2797(76)90010-7
更新日期：1976-04-01 00:00:00
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journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(78)90090-x
更新日期：1978-12-01 00:00:00
abstract：:A natural ursolic compound, 2β, 3β, 23-trihydroxy-urs-12-ene-28-olic acid (TUA) was isolated from the root of Actinidia chinensis Planch (A. chinensis Radix). Since a large number of triterpenoid compound has marked anticancer effects toward various types of cancer cell lines in vitro, this study was carried out to in...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2015.06.038
更新日期：2015-10-05 00:00:00
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journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2013.08.016
更新日期：2013-11-25 00:00:00
abstract：:Deoxypodophyllotoxin (DPT) is a naturally occurring flavolignan in Anthriscus sylvestris known as cow parsley or wild chervil, and has been reported to have inhibitory effects against several pathological processes including cancer, inflammation and infection. Here, we report the effects of DPT in the fatty liver indu...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2018.08.025
更新日期：2018-10-01 00:00:00
abstract：:Exposure to metals and metalloids including arsenic, cadmium, mercury, and nickel has been a worldwide health problem for several decades. The aim of this study was to learn how metal-induced oxidative stress triggers cell proliferation, a process of great significance for cancer. NADPH oxidase (NOX) activity and cell...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2014.10.034
更新日期：2014-12-05 00:00:00
abstract：:Butyrylcholinesterase (BChE) is the leading pretreatment candidate against exposure to organophosphates (OPs), which pose an ever increasing public and military health. Since respiratory failure is the primary cause of death following acute OP poisoning, an inhaled BChE therapeutic could prove highly efficacious in pr...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2012.11.004
更新日期：2013-03-25 00:00:00
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journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/s0009-2797(85)80166-6
更新日期：1985-07-01 00:00:00
abstract：:It was estimated, in a rat model of moderate and relatively high chronic human exposure to cadmium (Cd), whether enhanced zinc (Zn) consumption may prevent Cd-induced liver injury and if the possible protective effect of this bioelement depends on its intake. For this purpose, the structure and function of the liver o...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2011.05.008
更新日期：2011-09-30 00:00:00
abstract：:The feasibility of an oxygen-independent mechanism of chloroform bioactivation was indicated by the covalent binding to lipid and protein occurring in anaerobic incubations of CHCl3 and microsomes in the presence of NADPH. Under these conditions, the loss of cytochrome P-450 and the inhibition of related monoxygenases...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/s0009-2797(86)80063-1
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journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/s0009-2797(99)00025-3
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journal_title：Chemico-biological interactions
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更新日期：2020-06-01 00:00:00
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journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2015.06.022
更新日期：2015-09-05 00:00:00
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journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2005.10.008
更新日期：2005-12-15 00:00:00
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journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(85)90009-2
更新日期：1985-12-31 00:00:00
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journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2005.10.031
更新日期：2005-12-15 00:00:00
abstract：:Andrographolide (Andro), a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata, is known to possess multiple pharmacological activities. In our previous study, Andro had been shown to have potent anti-cancer activity against human colorectal carcinoma Lovo cells by inhibiting cell-c...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2009.04.011
更新日期：2009-08-14 00:00:00
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journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(90)90025-i
更新日期：1990-01-01 00:00:00
abstract：:At pH 7.35, N-(2-oxopropyl)-N-nitrosourea (OPNU) reacted with calf thymus DNA to yield O6-methylguanine, 7-methylguanine and 3-methyladenine. Kinetic measurements of the base catalyzed decomposition of OPNU and the extent of methylation of DNA by OPNU suggested that methylnitrosourea is not formed as an intermediate p...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(84)90118-2
更新日期：1984-02-01 00:00:00
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journal_title：Chemico-biological interactions
pub_type： 杂志文章
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更新日期：1987-01-01 00:00:00
abstract：:Quantum dots (QDs) are highly promising nanomaterials in bioimaging system because of their bright fluorescence, broad UV excitation, narrow emission band, and high photostability. Recently, there is a great activity on Ag2S quantum dots for both imaging and drug/gene delivery due to the potential of having a better c...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2018.06.032
更新日期：2018-08-01 00:00:00
abstract：:Tumor angiogenesis and PI3K/Akt/mTOR pathway are two major molecular objectives for the treatment and management of breast cancer. Here we first time report the molecular mechanism of a marine sponge alkaloid derivative 4-chloro fascapysin (4-CF) for its anticancer and antiangiogenesis potential. It simultaneously tar...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2017.07.017
更新日期：2017-09-25 00:00:00
