Chan ECY
Prenatal diet, plasma micronutrients/metabolome and inflammatory status influence the development of atopic eczema in early childhood
Not available.
ReadDirect and Sequential Bioactivation of Pemigatinib to Reactive Iminium Ion Intermediates Culminate in Mechanism-Based Inactivation of Cytochrome P450 3A
Significance Statement In this study, we reported for the first time the covalent MBI of CYP3A by PEM and deciphered its bioactivation pathway involving the metabolic activation of PEM and its major O-desmethylated metabolite to reactive iminium ion intermediates. Following which, a unique covalent docking methodology was harnessed to unravel the structural and molecular determinants underpinning its inactivation. Findings from our study lay the foundation for future investigation of clinically-relevant drug-drug interactions between PEM and concomitant substrates of CYP3A.
ReadDirect and Sequential Bioactivation of Pemigatinib to Reactive Iminium Ion Intermediates Culminate in Mechanism-Based Inactivation of Cytochrome P450 3A
In this study, we reported for the first time the covalent MBI of CYP3A by PEM and deciphered its bioactivation pathway involving the metabolic activation of PEM and its major O-desmethylated metabolite to reactive iminium ion intermediates. Following which, a unique covalent docking methodology was harnessed to unravel the structural and molecular determinants underpinning its inactivation. Findings from our study lay the foundation for future investigation of clinically-relevant drug-drug interactions between PEM and concomitant substrates of CYP3A.
ReadInfigratinib is a Reversible Inhibitor and Mechanism-based Inactivator of Cytochrome P450 3A4
Infigratinib (INF) is a promising selective inhibitor of fibroblast growth factor receptors 1-3 that has recently been accorded both orphan drug designation and priority review status by the U.S Food and Drug Administration for the treatment of advanced cholangiocarcinoma.
ReadDifferential Reversible and Irreversible Interactions between Benzbromarone and Human Cytochrome P450s 3A4 and 3A5
Mounting evidence have revealed that despite the high degree of sequence homology between cytochrome P450 3A isoforms (i.e. CYP3A4 and CYP3A5), they have the propensities to exhibit vastly different irreversible and reversible interactions with a single substrate. We have previously established that benzbromarone (BBR), a potent uricosuric agent utilized in the management of gout, irreversibly inhibits CYP3A4 via mechanism-based inactivation (MBI).
ReadAtypical kinetics of cytochrome P450 2J2: epoxidation of arachidonic acid and reversible inhibition by xenobiotic inhibitors
Extrahepatic CYP2J2 metabolism of arachidonic acid (AA) to bioactive regioisomeric epoxyeicosatrienoic acids (EETs) is implicated in both physiological and pathological conditions. Here, we aimed to characterize atypical substrate inhibition kinetics of this endogenous metabolic pathway and its reversible inhibition by xenobiotic inhibitors when AA is used as the physiologically-relevant substrate vis-à-vis conventional probe substrate astemizole (AST).
ReadMechanism-based Inactivation of Cytochrome P450 3A4 by Benzbromarone
Benzbromarone (BBR), a potent uricosuric agent for the management of gout, is known to cause fatal fulminant hepatitis. While the mechanism of BBR-induced idiosyncratic hepatotoxicity remains unelucidated, cytochrome P450 enzyme (CYP450)-mediated bioactivation of BBR to electrophilic reactive metabolites is commonly regarded as a key molecular-initiating event.
ReadSlow tight binding inhibition of CYP17A1 by abiraterone redefines its kinetic selectivity and dosing regimen
Substantial evidence underscores the clinical efficacy of inhibiting cytochrome P450 17A1 (CYP17A1)-mediated androgen biosynthesis by abiraterone for treatment of prostate oncology. Previous structural analysis and in vitro assays revealed inconsistencies surrounding the nature and potency of CYP17A1 inhibition by abiraterone.
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