FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2000241851> ?p ?o ?g. }

• W2000241851 endingPage "1612" @default.
• W2000241851 startingPage "1603" @default.
• W2000241851 abstract "Compound A (Cmpd A) was previously reported to form p-chlorophenyl isocyanate (CPIC), which was trapped by GSH to yield S- (N- [p-chlorophenyl] carbamoyl) glutathione adduct (SCPG) in the presence of human liver microsomes. In this study, P450 3A4 and 2C9 were demonstrated to be the enzymes mediating the activation of Cmpd A to CPIC in human liver microsomes based on inhibitory and correlation studies. Enzyme kinetics studies indicated that P450 3A4 was the primary enzyme involved in the activation of Cmpd A. In silico P450 3A4 active site docking of Cmpd A exhibited a low energy pose that orientated the pyrazole ring proximate to the heme iron atom, in which the distance between the C-3 and potential activated oxygen species was shown to be 3.4 A. Quantum molecular calculations showed that the electron density on C-3 was relatively higher than those on C-4 and C-5. These measurements suggested that the C-3 of Cmpd A was the preferred site of oxidation and hence predisposed Cmpd A in forming CPIC as previously proposed. The in silico prediction was corroborated by studies with the C-3 substituted analogue (methyl at C-3), which showed minimal conversion to CPIC in human liver microsomes. These results demonstrated a pivotal role for P450 3A4 in bioactivating Cmpd A by oxidizing at C-3 of the pyrazoline, hence facilitating the CPIC formation. Evidence of the bioactivation to CPIC in vivo was obtained by liquid chromatography-mass spectrometry (LC/MS) analysis of urine samples from human subjects administered a structural analogue of Cmpd A. The presence of S-(N-[p-chlorophenyl] carbamoyl) N-acetyl l-cysteine (SCPAC) as well as p-chlorophenyl aniline (CPA) was unequivocally demonstrated in the urine samples. The chemical scaffold, 4,5-dihydropyrazole-1-carboxylic acid-[(4-chlorophenyl)-amide], was demonstrated to possess potential metabolic liability in forming a reactive intermediate, CPIC, in humans. Bioactivation to CPIC may cause undesirable side effects through its reactivity and subsequent conversion to CPA, an established rodent carcinogen." @default.
• W2000241851 created "2016-06-24" @default.
• W2000241851 creator A5018297543 @default.
• W2000241851 creator A5022499603 @default.
• W2000241851 creator A5030528038 @default.
• W2000241851 creator A5035085963 @default.
• W2000241851 creator A5056628506 @default.
• W2000241851 creator A5059207255 @default.
• W2000241851 date "2009-08-21" @default.
• W2000241851 modified "2023-09-24" @default.
• W2000241851 title "Characterization of Cytochrome P450-Mediated Bioactivation of a Compound Containing the Chemical Scaffold, 4,5-Dihydropyrazole-1-carboxylic acid-(4-chlorophenyl amide), to a Chemically Reactive <i>p</i>-Chlorophenyl Isocyanate Intermediate in Human Liver Microsomes" @default.
• W2000241851 cites W1257197030 @default.
• W2000241851 cites W1482264334 @default.
• W2000241851 cites W1895993106 @default.
• W2000241851 cites W1967684747 @default.
• W2000241851 cites W1973291113 @default.
• W2000241851 cites W1977467384 @default.
• W2000241851 cites W1993558201 @default.
• W2000241851 cites W2011163792 @default.
• W2000241851 cites W2014919794 @default.
• W2000241851 cites W2018683888 @default.
• W2000241851 cites W2022981703 @default.
• W2000241851 cites W2025645149 @default.
• W2000241851 cites W2028908020 @default.
• W2000241851 cites W2033449111 @default.
• W2000241851 cites W2043445707 @default.
• W2000241851 cites W2058172465 @default.
• W2000241851 cites W2060245731 @default.
• W2000241851 cites W2060301655 @default.
• W2000241851 cites W2061835032 @default.
• W2000241851 cites W2074817502 @default.
• W2000241851 cites W2079955128 @default.
• W2000241851 cites W2086054530 @default.
• W2000241851 cites W2090335349 @default.
• W2000241851 cites W2090876589 @default.
• W2000241851 cites W2094412093 @default.
• W2000241851 cites W2101016189 @default.
• W2000241851 cites W2105902511 @default.
• W2000241851 cites W2109521216 @default.
• W2000241851 cites W2116459155 @default.
• W2000241851 cites W2124832527 @default.
• W2000241851 cites W2139853940 @default.
• W2000241851 cites W2145137957 @default.
• W2000241851 cites W2151930658 @default.
• W2000241851 cites W2163149841 @default.
• W2000241851 cites W2180600996 @default.
• W2000241851 cites W2482247887 @default.
• W2000241851 cites W2952688862 @default.
• W2000241851 cites W3021092633 @default.
• W2000241851 doi "https://doi.org/10.1021/tx900167y" @default.
• W2000241851 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/19697924" @default.
• W2000241851 hasPublicationYear "2009" @default.
• W2000241851 type Work @default.
• W2000241851 sameAs 2000241851 @default.
• W2000241851 citedByCount "6" @default.
• W2000241851 countsByYear W20002418512013 @default.
• W2000241851 countsByYear W20002418512018 @default.
• W2000241851 crossrefType "journal-article" @default.
• W2000241851 hasAuthorship W2000241851A5018297543 @default.
• W2000241851 hasAuthorship W2000241851A5022499603 @default.
• W2000241851 hasAuthorship W2000241851A5030528038 @default.
• W2000241851 hasAuthorship W2000241851A5035085963 @default.
• W2000241851 hasAuthorship W2000241851A5056628506 @default.
• W2000241851 hasAuthorship W2000241851A5059207255 @default.
• W2000241851 hasConcept C108204754 @default.
• W2000241851 hasConcept C161790260 @default.
• W2000241851 hasConcept C178790620 @default.
• W2000241851 hasConcept C181199279 @default.
• W2000241851 hasConcept C185592680 @default.
• W2000241851 hasConcept C192937433 @default.
• W2000241851 hasConcept C21951064 @default.
• W2000241851 hasConcept C2777682936 @default.
• W2000241851 hasConcept C2778439535 @default.
• W2000241851 hasConcept C2779578285 @default.
• W2000241851 hasConcept C2780534471 @default.
• W2000241851 hasConcept C41183919 @default.
• W2000241851 hasConcept C526171541 @default.
• W2000241851 hasConcept C55493867 @default.
• W2000241851 hasConcept C71240020 @default.
• W2000241851 hasConcept C86745063 @default.
• W2000241851 hasConcept C87644729 @default.
• W2000241851 hasConceptScore W2000241851C108204754 @default.
• W2000241851 hasConceptScore W2000241851C161790260 @default.
• W2000241851 hasConceptScore W2000241851C178790620 @default.
• W2000241851 hasConceptScore W2000241851C181199279 @default.
• W2000241851 hasConceptScore W2000241851C185592680 @default.
• W2000241851 hasConceptScore W2000241851C192937433 @default.
• W2000241851 hasConceptScore W2000241851C21951064 @default.
• W2000241851 hasConceptScore W2000241851C2777682936 @default.
• W2000241851 hasConceptScore W2000241851C2778439535 @default.
• W2000241851 hasConceptScore W2000241851C2779578285 @default.
• W2000241851 hasConceptScore W2000241851C2780534471 @default.
• W2000241851 hasConceptScore W2000241851C41183919 @default.
• W2000241851 hasConceptScore W2000241851C526171541 @default.
• W2000241851 hasConceptScore W2000241851C55493867 @default.
• W2000241851 hasConceptScore W2000241851C71240020 @default.
• W2000241851 hasConceptScore W2000241851C86745063 @default.
• W2000241851 hasConceptScore W2000241851C87644729 @default.

• next