Abstract：
:Because of the inability to predict and quantify the risk of idiosyncratic adverse drug reactions (IADRs) and because reactive metabolites (RMs) as opposed to the parent molecules from which they are derived are thought to be responsible for the pathogenesis of some IADRs, procedures (RM trapping/covalent binding) are being incorporated into the discovery screening funnel early-on to assess the risk of RM formation. Utility of the methodology in structure-toxicity relationships and scope in abrogating RM formation at the lead optimization stage are discussed in this article. Interpretation of the output from RM assessment assays, however, is confounded by the fact that many successfully marketed drugs are false positives. Therefore, caution must be exercised in deprioritizing a compound based on a positive result, so that the development of a useful and potentially profitable compound won't be unnecessarily halted. Risk mitigation strategies (e.g., competing detoxication pathways, low daily dose, etc.) when selecting RM positives for clinical development are also reviewed.
journal_name
Chem Biol Interactjournal_title
Chemico-biological interactionsauthors
Kalgutkar ASdoi
10.1016/j.cbi.2010.09.003subject
Has Abstractpub_date
2011-06-30 00:00:00pages
46-55issue
1-2eissn
0009-2797issn
1872-7786pii
S0009-2797(10)00547-8journal_volume
192pub_type
杂志文章abstract：:In comparison with the fluorescence emission spectra of 7-methylbenz[a]-anthracene-nucleoside adducts, the fluorescence emission spectra of hydrocarbon-deoxyribonucleoside adducts containing a methyl substituent in the "bay region" lack spectral resolution at room temperature and appear at substantially longer wavelen...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(79)90150-9
更新日期：1979-09-01 00:00:00
abstract：:The anticancer prodrug CPT-11 is a highly effective camptothecin analog that has been approved for the treatment of colon cancer. The 2.6 angstroms resolution crystal structure of its complex with Torpedo californica acetylcholinesterase (TcAChE) demonstrates that CPT-11 binds to TcAChE and spans its gorge similarly t...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2005.10.016
更新日期：2005-12-15 00:00:00
abstract：:A single intravenous injection of methylazoxymethanol (MAM) acetate in doses of either 20 or 35 mg/kg body weight to male Sprague-Dawley rats induced altered liver cell foci and later, liver neoplasms in a dose related manner. Sequential observations in the rats given 35 mg/kg and thereafter fed an iron-loading diet r...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/s0009-2797(86)80083-7
更新日期：1986-04-01 00:00:00
abstract：:Two homogenous fractions of hepatic metallothioneins ((Cd,Zn) MT-1 and (Cd,Zn) MT-2) and renal metal binding proteins ((Bi,Cu) BP-1 and (Bi,Cu) BP-2) were isolated from rats exposed to heavy metals and specific antisera to them were produced in rabbits. These antisera were tested by immunodiffusion and immunoelectroph...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(80)90048-4
更新日期：1980-12-01 00:00:00
abstract：BACKGROUND:Head and neck squamous cell carcinoma (HNSCC) is one of the most common lethal tumors with a high recurrence rate and low survival rate. Therefore, an urgent need exists for novel and effective treatment strategies for HNSCC patients. METHODS:Osthole, a natural ingredient extracted from Cnidium monnieri (L....
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2019.108934
更新日期：2020-01-25 00:00:00
abstract：:Pyrethroid interactions with dipalmitoyl phosphatidylcholine (DPPC) vesicles have been characterized in bilayers having large and small radii of curvature. The abilities of pyrethroids to alter the gel-fluid phase transition profiles were determined by steady state fluorescence anisotropy and phase-modulation lifetime...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/s0009-2797(85)80156-3
更新日期：1985-06-01 00:00:00
abstract：:Neurotoxicity is a key dose-limiting factor for colistin therapy. This study aimed to investigate the protective effect of Salidroside on colistin-induced neurotoxicity in RSC96 Schwann cells and the underlying mechanisms. After Salidroside (12.5, 25, 50 μg/mL) treatment for 2 h, the cells were cultured with 250 μg/mL...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2017.04.027
更新日期：2017-06-01 00:00:00
abstract：:Hepatic injury remains not only the commonest reason for the termination of drugs in their pre-clinical development but is also the most frequent reason for the withdrawal of approved drugs from the market. Mitochondria are the central point where the different signals responsible for initiating hepatocyte cell death ...
journal_title：Chemico-biological interactions
pub_type： 杂志文章,评审
doi：10.1016/j.cbi.2006.06.007
更新日期：2006-10-27 00:00:00
abstract：:Drug induced liver injury (DILI), a major cause of pre- and post-approval failure, is challenging to predict pre-clinically due to varied underlying direct and indirect mechanisms. Nevirapine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) and Ritonavir, a protease inhibitor, are antiviral drugs that cause c...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2015.11.023
更新日期：2016-08-05 00:00:00
abstract：:The Syrian hamster Harderian gland (HG), representing a highly porphyrogenic organ, was used as a model system for studying physiologically occurring damage of biomolecules by porphyrins and their precursors, phenomena associated with from the pathological situation of porphyrias. The species used exhibits the peculia...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/s0009-2797(00)00320-3
更新日期：2001-04-16 00:00:00
abstract：:The mutagenicity of many 2-aminoimidazole-azaarenes (AIA) is thought to be mediated by the nitrenium form of the exocyclic amine. This hypothesis is supported by the numerous correlations found between calculated and experimentally-measured chemical properties for the nitreniums and the mutagenic potencies of the nitr...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/s0009-2797(97)00094-x
更新日期：1997-12-12 00:00:00
abstract：:MnFe2O4 nanoparticles (NPs) are commonly produced in some occupational settings and may reach high concentration in activities such as arc-welding or ferroalloy metallurgy. Manganese is an essential cofactor in enzyme activities but it has been demonstrated that long-term exposure to excessive levels can lead to "mang...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2018.07.020
更新日期：2018-09-25 00:00:00
abstract：:Endocrine therapies (e.g. tamoxifen and aromatase inhibitors) targeting estrogen action are effective in decreasing mortality of breast cancer. However, their efficacy is limited by intrinsic and acquired resistance. Our previous study demonstrated that overexpression of a histone methyltransferase NSD2 drives tamoxif...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2020.108965
更新日期：2020-02-01 00:00:00
abstract：:Numerous reactive oxygen species (ROS) and reactive carbonyl species (RCS) issuing from lipid and sugar oxidation are known to damage a large number of proteins leading to enzyme inhibition and alteration of cellular functions. Whereas studies in literature only focus on the reactivity of one or two of these compounds...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2010.12.028
更新日期：2011-03-15 00:00:00
abstract：:A novel post-addition method, based on the trapping of ABTS-radicals, is applied for studying the total antioxidant capacity of seminal plasma. A remarkable profile is observed, in which seminal plasma quenches radicals in a continuous, relatively slow fashion. Five putative antioxidants present in seminal plasma were...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/s0009-2797(00)00179-4
更新日期：2000-07-03 00:00:00
abstract：:Using a rat liver cytosol source of enzyme trialkyl phosphorothioates have been shown to be substrates of glutathione S-transferases. Using OSS-trimethyl phosphorodithioate (OSS-Me(O] and OOS-trimethyl phosphorothioate (OOS-Me(O] the methyl transferred to the sulphydryl of glutathione is that attached to phosphorus vi...
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：:The atypical butyrylcholinesterase (aBuChE) from Oryzias latipes shares approximately 65% sequence similarity to both acetylcholinesterase and butyrylcholinesterase and was studied for its capacity to spontaneously reactivate following inhibition by organophosphorus nerve agents. Like other cholinesterases, aBuChE was...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2016.03.016
更新日期：2016-11-25 00:00:00
abstract：:A series of new ionic Pt(II) complexes of general formula [Pt(II)(A)n(Cl)(AO)]X (A=en, NH3; n=1, 2; X-=BF4-, NO3-, PF6-, CF3SO3-), 1-5, containing Acridine Orange (AO) bound to the metal atom through the endocyclic N atom, have been tested in human melanoma cells (M14, JR8 and PLF2), human neuroblastoma cell line SH-S...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2006.03.011
更新日期：2006-07-10 00:00:00
abstract：:Green tea catechins (GTCs) are polyphenolic flavonoids formerly called vitamin P. GTCs, especially (-)-epigallocatechin-3-gallate (EGCG), lower the incidence of cancers, collagen-induced arthritis, oxidative stress-induced neurodegenerative diseases, and streptozotocin-induced diabetes. Also, inhibition of adipogenesi...
journal_title：Chemico-biological interactions
pub_type： 杂志文章,评审
doi：10.1016/j.cbi.2007.02.008
更新日期：2007-04-25 00:00:00
abstract：:Administration of a single oral dose of dieldrin (20 mg/kg body wt.) to rhesus monkeys considerably elevated the uptake of glucose and the activities of brush border sucrase, lactase, maltase and alkaline phosphatase in intestine compared to control animals. Leucine uptake and leucine amino peptidase activity was sign...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(81)90173-3
更新日期：1981-10-01 00:00:00
abstract：BACKGROUND AND AIM:This study aimed to evaluate the in vivo antitumor actions and toxicity of the dichloromethane fraction (F1B) of Moquiniastrum polymorphum subsp. floccosum (formerly Gochnatia polymorpha ssp. floccosa), composed of sesquiterpene lactones, against Walker-256 carcinosarcoma in rats. METHODS:Male Wista...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2015.01.018
更新日期：2015-02-25 00:00:00
abstract：:The metabolism and genotoxicity of 1,2-dibromoethane (EDB) and its deuterium substituted analog ( d4EDB ) were studied in isolated rat hepatocytes. There was a marked isotope effect on the metabolism of EDB by hepatocytes. This was due to decreased microsomal oxidation of d4EDB . Cytosolic metabolism of EDB, as measur...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(84)90063-2
更新日期：1984-04-01 00:00:00
abstract：:Human carbonyl reductases 1 and 3 (CBR1 and CBR3) are monomeric NADPH-dependent enzymes of the short-chain dehydrogenase/reductase superfamily. Despite 72% identity in primary structure they exhibit substantial differences in substrate specificity. Recently, the endogenous low molecular weight S-nitrosothiol S-nitroso...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2011.01.016
更新日期：2011-05-30 00:00:00
abstract：:A microspectrophotometric method for assaying cytochrome P-450 in fresh 24 micrometer unfixed cryostat sections of rat liver has been developed. When used to assay this cytochrome in sections of microsomal preparations it has yielded results equivalent to those obtained by the conventional spectrophotometric assay of ...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(78)90108-4
更新日期：1978-03-01 00:00:00
abstract：:Increasing evidence has shown that dysregulation of microRNA-621 (miR-621) is demonstrated to be associated with several cancers. However, the role of miR-621 in bladder cancer (BCa) remains unclear. Herein, we aimed to study the expression pattern, biological function, and molecular mechanism of miR-621 in BCa. First...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2019.05.042
更新日期：2019-08-01 00:00:00
abstract：:The 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethene (DDT) metabolic intermediate 1-chloro-2,2-bis(p-chlorophenyl)ethene (DDMU) is partially metabolized in vivo by mice to 2-hydroxy-2,2-bis(p-chlorophenyl)acetic acid (alpha OH-DDA) and other metabolites which are excreted in urine. The subsequent DDT metabolic intermedia...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(81)90140-x
更新日期：1981-05-01 00:00:00
abstract：:A variety of substances of diverse structure have been shown to affect the activity of protein kinase C. Many of the agents which affect protein kinase C activity also markedly shift the bilayer to hexagonal phase transition temperature of phosphatidylethanolamines. Although one of the more potent activators of protei...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(87)90044-5
更新日期：1987-01-01 00:00:00
abstract：:Chaetocin is a natural product isolated from Chaetomium species that has anti-bacterial and anti-myeloma activities. In this study, we investigated the inhibitory effect of chaetocin on melanogenesis and the underlying mechanisms in B16F10 mouse melanoma cells. In the present study, chaetocin significantly inhibited I...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2015.12.021
更新日期：2016-02-05 00:00:00
abstract：:The functional genetic polymorphism of aldehyde dehydrogenase 2 (ALDH2) influences the enzymatic activities of its wild type (Glu504 encoded by ALDH2*1) and mutant type (Lys504 encoded by ALDH2*2) proteins. The enzymatic activities of mutant-type ALDH2 are limited compared with those of the wild type. ALDH2 has been s...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2017.03.012
更新日期：2017-10-01 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
