Abstract:
:A pulsed ultrafiltration-mass spectrometric screening assay has been developed to generate and identify electrophilic metabolites of xenobiotic compounds formed by hepatic cytochrome P450 enzymes. This assay would be suitable for the early identification of potentially toxic compounds during the initial phase of drug development. Rat liver microsomes were trapped by an ultrafiltration membrane in a stirred flow-through chamber, and substrates for microsomal cytochrome P450 including hydroxychavicol, 3-methylindole, cyproheptadine and 2-tert-butyl-4,6-dimethylphenol were flow-injected individually through the chamber along with the cofactors, NADPH and glutathione. Metabolites and glutathione conjugates were detected on-line using electrospray mass spectrometry. Alternatively, the ultrafiltrate was concentrated on a reversed phase HPLC column and analyzed using electrospray LC-MS or LC-MS-MS to separate and characterize isomeric metabolites and metabolites present at low concentration. Enzymatic activation of each xenobiotic substrate produced highly electrophilic metabolites such as quinones, quinone methides and imine methides that reacted with glutathione on-line to produce glutathione conjugates which were detected by using electrospray mass spectrometry. Although epoxides such as cyproheptadine epoxide were generated, it is likely that these compounds were insufficiently reactive to form glutathione conjugates in the absence of cytosolic glutathione S-transferases. Pulsed ultrafiltration-electrospray mass spectrometry offers an efficient method for in vitro formation and mass spectrometric characterization of activated microsomal drug metabolites and is suitable for use during the drug discovery process for the early identification and screening out of potentially toxic lead compounds.
journal_name
Comb Chem High Throughput Screenjournal_title
Combinatorial chemistry & high throughput screeningauthors
Nikolic D,Fan PW,Bolton JL,van Breemen RBsubject
Has Abstractpub_date
1999-06-01 00:00:00pages
165-75issue
3eissn
1386-2073issn
1875-5402journal_volume
2pub_type
杂志文章abstract:OBJECTIVE:A significant proportion of patients with early non-small cell lung cancer (NSCLC) can be cured by surgery. The distant metastasis of tumors is the most common cause of treatment failure. Precisely predicting the likelihood that a patient develops distant metastatic risk will help identify patients who can fu...
journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
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更新日期:2019-01-01 00:00:00
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journal_title:Combinatorial chemistry & high throughput screening
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journal_title:Combinatorial chemistry & high throughput screening
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journal_title:Combinatorial chemistry & high throughput screening
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journal_title:Combinatorial chemistry & high throughput screening
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journal_title:Combinatorial chemistry & high throughput screening
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journal_title:Combinatorial chemistry & high throughput screening
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journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章,评审
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journal_title:Combinatorial chemistry & high throughput screening
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journal_title:Combinatorial chemistry & high throughput screening
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journal_title:Combinatorial chemistry & high throughput screening
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更新日期:2010-11-01 00:00:00
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journal_title:Combinatorial chemistry & high throughput screening
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更新日期:2011-05-01 00:00:00
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journal_title:Combinatorial chemistry & high throughput screening
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更新日期:2005-12-01 00:00:00
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journal_title:Combinatorial chemistry & high throughput screening
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journal_title:Combinatorial chemistry & high throughput screening
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journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章
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更新日期:2012-12-01 00:00:00
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journal_title:Combinatorial chemistry & high throughput screening
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更新日期:2002-02-01 00:00:00
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journal_title:Combinatorial chemistry & high throughput screening
pub_type: meta分析
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更新日期:2020-10-20 00:00:00
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journal_title:Combinatorial chemistry & high throughput screening
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journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章,评审
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journal_title:Combinatorial chemistry & high throughput screening
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journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章,评审
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更新日期:2015-01-01 00:00:00
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journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章,评审
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更新日期:2001-08-01 00:00:00
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journal_title:Combinatorial chemistry & high throughput screening
pub_type: 杂志文章,评审
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更新日期:2001-05-01 00:00:00
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journal_title:Combinatorial chemistry & high throughput screening
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更新日期:2014-01-01 00:00:00
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journal_title:Combinatorial chemistry & high throughput screening
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更新日期:2004-02-01 00:00:00
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journal_title:Combinatorial chemistry & high throughput screening
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更新日期:2016-01-01 00:00:00
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journal_title:Combinatorial chemistry & high throughput screening
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更新日期:2020-01-01 00:00:00
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journal_title:Combinatorial chemistry & high throughput screening
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更新日期:2020-10-23 00:00:00
abstract::Artificial neural networks (ANNs) have been applied for the quantitative structure-activity relationships (QSAR) studies of antibacterial activity against Escherichia coli, Serratia marcescens, Proteus vulgaris, Klebsiella pneumoniae and Pseudomonas aeruginosa of a large series of new imidazole derivatives. Antibacter...
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更新日期:2004-06-01 00:00:00