In VitroInhibition of Huanglian [Rhizoma coptidis(L.)] and its Six Active Alkaloids on Six Cytochrome P450 Isoforms in Human Liver Microsomes

ABSTRACT The inhibitory effect of chloramphenicol on human cytochrome P450 (CYP) isoforms was evaluated with human liver microsomes and cDNA-expressed CYPs. Chloramphenicol had a potent inhibitory effect on CYP2C19-catalyzed S-mephytoin 4′-hydroxylation and CYP3A4-catalyzed midazolam 1-hydroxylation, with apparent 50% inhibitory concentrations (inhibitory constant [Ki ] values are shown in parentheses) of 32.0 (7.7) and 48.1 (10.6) μM, respectively. Chloramphenicol also weakly inhibited CYP2D6, with an apparent 50% inhibitory concentration (Ki ) of 375.9 (75.8) μM. The mechanism of the drug interaction reported between chloramphenicol and phenytoin, which results in the elevation of plasma phenytoin concentrations, is clinically assumed to result from the inhibition of CYP2C9 by chloramphenicol. However, using human liver microsomes and cDNA-expressed CYPs, we showed this interaction arises from the inhibition of CYP2C19- not CYP2C9-catalyzed phenytoin metabolism. In conclusion, inhibition of CYP2C19 and CYP3A4 is the probable mechanism by which chloramphenicol decreases the clearance of coadministered drugs, which manifests as a drug interaction with chloramphenicol.

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Ethanol oxidation into acetaldehyde by 16 recombinant human cytochrome P450 isoforms: Role of CYP2C isoforms in human liver microsomes

Toxicology Letters ◽

10.1016/j.toxlet.2006.09.011 ◽

2006 ◽

Vol 167 (3) ◽

pp. 221-230 ◽

Cited By ~ 20

Author(s):

S. Hamitouche ◽

J. Poupon ◽

Y. Dreano ◽

Y. Amet ◽

D. Lucas

Keyword(s):

Cytochrome P450 ◽

Human Liver ◽

Ethanol Oxidation ◽

Liver Microsomes ◽

Human Liver Microsomes ◽

Human Cytochrome ◽

Cytochrome P450 Isoforms

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In Vitro Metabolism Study of Seongsanamide A in Human Liver Microsomes Using Non-Targeted Metabolomics and Feature-Based Molecular Networking

Pharmaceutics ◽

10.3390/pharmaceutics13071031 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1031

Author(s):

Zhexue Wu ◽

Geum Jin Kim ◽

So-Young Park ◽

Jong Cheol Shon ◽

Kwang-Hyeon Liu ◽

...

Keyword(s):

Cytochrome P450 ◽

Metabolic Pathway ◽

Human Liver ◽

Liver Microsomes ◽

Human Liver Microsomes ◽

Targeted Metabolomics ◽

Molecular Networking ◽

Cytochrome P450 Isoforms ◽

Feature Based

Seongsanamide A is a bicyclic peptide with an isodityrosine residue discovered in Bacillus safensis KCTC 12796BP which exhibits anti-allergic activity in vitro and in vivo without significant cytotoxicity. The purpose of this study was to elucidate the in vitro metabolic pathway and potential for drug interactions of seongsanamide A in human liver microsomes using non-targeted metabolomics and feature-based molecular networking (FBMN) techniques. We identified four metabolites, and their structures were elucidated by interpretation of high-resolution tandem mass spectra. The primary metabolic pathway associated with seongsanamide A metabolism was hydroxylation and oxidative hydrolysis. A reaction phenotyping study was also performed using recombinant cytochrome P450 isoforms. CYP3A4 and CYP3A5 were identified as the major metabolic enzymes responsible for metabolite formation. Seongsanamide A did not inhibit the cytochrome P450 isoforms commonly involved in drug metabolism (IC50 > 10 µM). These results will contribute to further understanding the metabolism and drug interaction potential of various bicyclic peptides.

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