Abstract:
:We have analyzed gene expression and histopathology of rat liver treated with a histamine-3 receptor inverse agonist under development for the treatment of obesity 24 h after a single acute administration. While histopathology did not identify a clear liver toxicity, analysis of gene changes strongly suggested the development of toxicity. This prediction was confirmed in a 2-week repeat-dose rat study where prominent liver pathology occurred, while gene changes that lead to the prediction persisted. A subset of these genes was analyzed in vitro in both rat and human hepatocytes to reveal the potential relevancy of the findings for the situation in humans. This comprehensive analysis of the development compound at the gene expression level allowed interpretation of findings of the follow-up compound in a frontloaded 24-h single-dose acute study that was initiated before regular 2-week repeat-dose studies started. The high similarity of the follow-up compound to the lead compound based on gene expression lead to the immediate termination of the development program for this compound series. Our data demonstrate the value of genomics-based early toxicity prediction in short-term in vivo studies for the characterization of compounds to allow prioritization and selection of suited candidates before compound-, animal-, and cost-intensive longer term studies are undertaken.
journal_name
J Biochem Mol Toxicoljournal_title
Journal of biochemical and molecular toxicologyauthors
Roth A,Boess F,Landes C,Steiner G,Freichel C,Plancher JM,Raab S,de Vera Mudry C,Weiser T,Suter Ldoi
10.1002/jbt.20375subject
Has Abstractpub_date
2011-05-01 00:00:00pages
183-94issue
3eissn
1095-6670issn
1099-0461journal_volume
25pub_type
杂志文章abstract::The quantitative influence of copper on the interaction between cytochrome c and sulfite, which is a derivate of sulfur dioxide in the human body, has been studied by fluorescence spectrometry and ultraviolet absorption spectrometry in vitro. The results indicate that copper may intensely combine with protein componen...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.20143
更新日期:2006-01-01 00:00:00
abstract::Netrin-1 has been found to protect kidneys from ischemia/reperfusion injury. In this study, we aimed to address whether the protective effects were mediated through suppression of oxidative stress and neuropeptide Y. Compared to sham-operated animals, animals after ischemia/reperfusion showed marked kidney damage and ...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.21474
更新日期:2013-04-01 00:00:00
abstract::Retinoic acid (RA) alters the developmental fate of the axial skeletal anlagen. "Anteriorizations" or "posteriorizations," the assumption of characteristics of embryonic areas normally anterior or posterior to the affected tissues, are correlated with altered embryonal expression domains of Hox genes after in utero RA...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.10098
更新日期:2003-01-01 00:00:00
abstract::Reactive oxygen species (ROS) are generated as by-product of cellular respiration and also due to the exposure of various xenobiotics, whereas mitochondrial electron transport chain is considered as the main source of ROS generation. The sequential addition to molecular oxygen gives rise to various forms of ROS like s...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章,评审
doi:10.1002/jbt.22643
更新日期:2020-09-29 00:00:00
abstract::The present study was designed to elucidate the involvement of acid phosphatase (ACP) in metastasis and lactate dehydrogenase (LDH) as an immediate compensatory alleviation mechanism for energy stress in liver lesions induced by hexachlorocyclohexane in Swiss mice. Animals were continuously exposed to hexachlorocycloh...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.21441
更新日期:2012-11-01 00:00:00
abstract::The objective of the present study was to assess superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), paraoxonase (PON1), glutathione reductase (GR), and catalase (CAT) activities ratio and their relationship with DNA oxidative damage in rats treated with cisplatin (3 mg/kg bwt/day) in the presence and ...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.21501
更新日期:2013-08-01 00:00:00
abstract::β-Lactam antibiotics such as ceftriaxone, are potent stimulators of the expression of l-glutamate transporter GLT-1 and may exert neuroprotective effects when chronically used in rats and mice. In this study, we used two animal models to test the neurological effect of subchronic treatment with ceftriaxone: experiment...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.22578
更新日期:2020-11-01 00:00:00
abstract:BACKGROUND:Cadmium is a nonessential toxic heavy metal, which enters the body easily and damages the cellular system. The sonic hedgehog (Shh) signaling pathway is one of the key regulatory pathways, which define neural growth and development. OBJECTIVES:This study aimed to explore how cadmium exposure affects neural ...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.22274
更新日期:2019-04-01 00:00:00
abstract::The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that binds and mediates responses to many halogenated aromatic compounds (HACs). Exposure to mixtures of HACs frequently results in nonadditive behavior in both in vivo and in vitro assays. One cause is antagonism, which results when two or...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/(sici)1099-0461(2000)14:2<73::aid-jbt2>3.0
更新日期:2000-01-01 00:00:00
abstract::CYP1A1 and CYP1A2 enzymes metabolize polycyclic aromatic hydrocarbons (PAHs) to the reactive oxyderivatives. PAHs can induce the activity of both enzymes, which increases its conversion and enhances risk of carcinogenesis. Thus, the inhibition of CYP enzymes is recognized as a cancer chemoprevention strategy. A well-k...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.20259
更新日期:2009-01-01 00:00:00
abstract::Mitochondria play an important role in myocardial tissue homeostasis; therefore, deterioration in mitochondrial function will eventually lead to cardiomyocyte and endothelial cell death and consequently cardiovascular dysfunction. Lithium (Li+ ) is an effective drug for bipolar disorder with known cardiotoxic side eff...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.21836
更新日期:2017-02-01 00:00:00
abstract::Disruption of the balance oxidants, antioxidants cause various pathophysiological conditions such as lipid peroxidation, protein degradation, or DNA damage. We have examined possible effects of kisspeptin-10 on the structural damage produced by methionine-induced lipid peroxidation in testicle tissue of young rats. Ki...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.21881
更新日期:2017-05-01 00:00:00
abstract::The effects of benzo[a]pyrene (B[a]P) on some drug-metabolizing and antioxidant systems in liver, lung, and stomach were investigated in normal and protein malnutrition (PM) rats. PM significantly inhibited tissue glutathione (GSH) content and increased hepatic lipid peroxidation. Cytochrome P450 isoform CYP1A1 was si...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.10064
更新日期:2003-01-01 00:00:00
abstract::Manganese is an essential trace element found in many enzymes. As it is the case of many essential trace elements, excessive level of manganese is toxic. It has been proven that excessive manganese could cause heart problems. In order to understand the mechanism of manganese toxicity in the heart, the effects of manga...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.20133
更新日期:2006-01-01 00:00:00
abstract::Limited research has been performed on S-adenosylhomocysteine (SAH) or homocysteine (Hcy)-evoked cell damage in hepatic and neuronal cells. In this study, we assessed effects of SAH or Hcy on cell cytotoxicity and DNA damage in hepatic and neuronal cells and attempted to find the underlying mechanism. Cell cytotoxicit...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.20298
更新日期:2009-09-01 00:00:00
abstract::Zingerone (ZO), an active phenolic agent derived from Zingiber officinale (Ginger), has many pharmacological properties such as antioxidant, antiangiogenic, and antitumor. However, its potential value in cancer and the mechanism by which ZO wields its therapeutic effects remain obscure. Therefore, in this current stud...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.22403
更新日期:2019-12-01 00:00:00
abstract::Recent studies have established the importance of estrogen-related receptor γ (ERRγ) as a required participant for insulin secretion in pancreatic β cells. Key downstream genes of ERRγ remain unclear in the pancreatic β cell. To understand the molecular role of ERRγ and elucidate potential key candidate genes involved...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.22390
更新日期:2019-10-01 00:00:00
abstract::To date, microRNA-4709 (miR-4709) has not been studied in colon adenocarcinoma (COAD) on the basis of experiments. In our study, we aimed to investigate the biological roles and clinical significance of miR-4709 in COAD. The expression difference between miR-4709 and NR3C2 was measured based on The Cancer Genome Atlas...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.22411
更新日期:2019-12-01 00:00:00
abstract::Chalcones and chalcone epoxides are important synthetic intermediates in organic and medicinal chemistry. Chalcones possess a broad spectrum of biological activities; however, 1,3-diphenyl-2-propenone or chalcone has not been given the attention it deserve as its substituted derivatives. In this study, the inhibition ...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.22240
更新日期:2019-02-01 00:00:00
abstract::The early research found that the spiderlings of black widow spider (Latrodectus tredecimguttatus) exhibited obvious toxicity to animals. The present work performed a systematical analysis of the aqueous extract of newborn black widow spiderlings. The extract was shown to contain 69.42% of proteins varying in molecula...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.21553
更新日期:2014-05-01 00:00:00
abstract::Nitrofurantoin (N-(5-nitro-2-furfurylidine) 1-amino-hydantoine; NIT) is mainly used for the treatment of acute urinary tract infections. However, its administration can be associated with liver failure or cirrhosis. The aim of this study was to determine whether NIT is a mitochondrial toxicant, if so, what mechanism(s...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.21825
更新日期:2016-12-01 00:00:00
abstract::M1 macrophages serve one edge as proinflammatory and M2 macrophages serve the other edge as an anti-inflammatory macrophage. It appears that a related "switch" in macrophage morphology may also happen in the course of atherosclerosis, which has not yet been elucidated. An atherogenic diet (AD) was given to rats, and i...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.22422
更新日期:2020-02-01 00:00:00
abstract::Diabetic neuropathic pain is characterized by spontaneous pain with hyperalgesia and allodynia. We investigated whether (-)-epigallocatechin-3-O-gallate could improve diabetic neuropathic pain development through hypoglycemic, hypolipidemic, antioxidant, and anti-inflammatory effects. Diabetes was induced in rats by s...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.22508
更新日期:2020-08-01 00:00:00
abstract::The effects of ellagic acid (EA) and vitamin E succinate (VES) on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced oxidative stress in different brain regions of rats have been studied after subchronic exposure to the compounds. TCDD was administered to groups of rats at a dose of 46 ng/kg/day for 90 days. EA and VE...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.20030
更新日期:2004-01-01 00:00:00
abstract::We investigated the effects of chrysin (CHR) on nonalcoholic fatty liver disease (NAFLD) in mice. The NAFLD mouse model was established using a diet deficient in methionine and choline (MCD). CHR was shown to attenuate MCD-induced hepatic fat accumulation, increase very low-density lipoprotein (VLDL) secretion, and de...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.22497
更新日期:2020-07-01 00:00:00
abstract::Multiple sclerosis (MS) is a well-known neurodegenerative disorder, causing toxicity in different organs, such as spinal cord tissue. The goal of this study was to investigate the protective effect of ellagic acid (EA) against spinal cord and sciatica function in cuprizone (Cup)-induced demyelination model. Animals we...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.22564
更新日期:2020-11-01 00:00:00
abstract::The current work planned to assess the protecting properties of nimbolide against doxorubicin (DOX)-treated myocardial damage. Myocardial damage was produced with 2.5 mg/kg of DOX given on alternative days (14 days). Thiobarbituric acid reactive substances (TBARS) levels of a lipid peroxidative marker were elevated, w...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.22543
更新日期:2020-07-06 00:00:00
abstract::In the presence of trifluoroacetic acid, on the basis of three-component condensation of phenylthiourea with its salicylaldehyde and methyl-3-oxobutanoate, an efficient method for the synthesis of 1-(4-(2-hydroxyphenyl)-6-methyl-1-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl)ethanone (I) has been worked out. These...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.22221
更新日期:2018-12-01 00:00:00
abstract::Schisandrin A (SchA) has been reported as a multidrug resistance-reversing agent; however, its antitumor effects have been rarely reported. Consequently, we attempted to explore whether SchA per se possesses an antitumor property in choriocarcinoma JEG-3 and BeWo cells and its potential mechanisms. JEG-3, BeWo, and HT...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/jbt.22455
更新日期:2020-04-01 00:00:00
abstract::Effects of Cd2+ and two complexes of bivalent cadmium with 1,3-bis(4-chlorbenzylidenamino)-guanidine and anabasine on ion permeability of the inner membrane and respiration of isolated rat liver mitochondria were studied. Starting from 5 microM, Cd2+ decreased state 3 and DNP-stimulated respiration of mitochondria and...
journal_title:Journal of biochemical and molecular toxicology
pub_type: 杂志文章
doi:10.1002/(sici)1099-0461(1999)13:3/4<149::aid-jbt5>
更新日期:1999-01-01 00:00:00