scholarly journals Inhibitory Effect of Selaginellins from Selaginella tamariscina (Beauv.) Spring against Cytochrome P450 and Uridine 5′-Diphosphoglucuronosyltransferase Isoforms on Human Liver Microsomes

Molecules ◽  
2017 ◽  
Vol 22 (10) ◽  
pp. 1590 ◽  
Author(s):  
Jae-Kyung Heo ◽  
Phi-Hung Nguyen ◽  
Won Kim ◽  
Nguyen Phuc ◽  
Kwang-Hyeon Liu
Keyword(s):  
Cytochrome P450 ◽  
Human Liver ◽  
Liver Microsomes ◽  
Inhibitory Effect ◽  
Human Liver Microsomes ◽  
Selaginella Tamariscina

scholarly journals The Potential for CYP2D6 Inhibition Screening Using a Novel Scintillation Proximity Assay-Based Approach

2001 ◽  
Vol 6 (4) ◽  
pp. 225-231 ◽  
Author(s):  
Enock Delaporte ◽  
Donald E. Slaughter ◽  
Marjorie A. Egan ◽  
Gregory J. Gatto ◽  
Albie Santos ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
High Throughput ◽  
Human Liver ◽  
High Performance ◽  
Liver Microsomes ◽  
Inhibitory Effect ◽  
Human Liver Microsomes ◽  
Kinetics Parameters ◽  
Scintillation Proximity Assay ◽  
Demethylase Activity

High throughput inhibition screens for human cytochrome P450s (CYPs) are being used in preclinical drug metabolism to support drug discovery programs. The versatility of scintillation proximity assay (SPA) technology has enabled the development of a homogeneous high throughput assay for cytochrome P450 2D6 (CYP2D6) inhibition screen using [O-methyl-'4C]dextromethorphan as substrate. The basis of the assay was the trapping of the 0- demethylation product, [14C]HCHO, on SPA beads. Enzyme kinetics parameters Vm,,. and apparent Ki,, determined using pooled human liver microsomes and microsomes from baculovirus cells coexpressing human CYP2D6 and NADPH-cytochrome P450 reductase, were 245 pmol [14C]HCHO/min/mg protein and 11,tM, and 27 pmol ['4C]HCHO/min/pmol and 1.6,uM, respectively. In incubations containing either pooled microsomes or recombinant CYP2D6, [14C]dextromethorphan 0-demethylase activity was inhibited in the presence of quinidine (IC50 = 1.0,uM and 20 nM, respectively). By comparison, inhibitors selective for other CYP isoforms were relatively weak (IC50 > 25 tM). In agreement, a selective CYP2D6 inhibitory monoclonal antibody caused greater than 90% inhibition of [14C]dextromethorphan O-demethylase activity in human liver microsomes, whereas CYP2C9/19- and CYP3A4/5-selective antibodies elicited a minimal inhibitory effect. SPA-based [14C]dextromethorphan 0-demethylase activity was also shown to correlate (r2 = 0.6) with dextromethorphan O-demethylase measured by high-performance liquid chromatography in a bank of human liver microsomes (N = 15 different organ donors). In a series of known CYP2D6 inhibitors/substrates, the SPA-based assay resolved potent inhibitors (IC50 <2 μM) from weak inhibitors (IC50 ≥ 20 μM). It is concluded that the SPA-based assay described herein is suitable for CYP2D6 inhibition screening using either native human liver microsomes or cDNA-expressed CYP2D6.

scholarly journals Inhibitory effect of Loperamide on Cytochrome P450 3A4 in Human Liver Microsomes

2005 ◽  
Vol 13 (1) ◽  
pp. 84
Author(s):  
Myung-Sup Jeong ◽  
Tae-Ho Lee ◽  
Jeong-Woong Moon ◽  
Soon-Ok Byun ◽  
Ji-Young Park ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Human Liver ◽  
Liver Microsomes ◽  
Inhibitory Effect ◽  
Human Liver Microsomes ◽  
Cytochrome P450 3A4

scholarly journals The Inhibitory Effect of Amoxapine on Cytochrome P450 Enzyme Activity in Human Liver Microsomes

2004 ◽  
Vol 16 (4) ◽  
pp. 329-338 ◽  
Author(s):  
Eriko SAKURAI ◽  
Mariko IWASE ◽  
Norimitsu KURATA ◽  
Tomoko NAGAI ◽  
Hayato HIRASHIMA ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Cytochrome P450 ◽  
Human Liver ◽  
Liver Microsomes ◽  
Inhibitory Effect ◽  
Human Liver Microsomes ◽  
Cytochrome P450 Enzyme ◽  
P450 Enzyme

scholarly journals Chloramphenicol Is a Potent Inhibitor of Cytochrome P450 Isoforms CYP2C19 and CYP3A4 in Human Liver Microsomes

2003 ◽  
Vol 47 (11) ◽  
pp. 3464-3469 ◽  
Author(s):  
Ji-Young Park ◽  
Kyoung-Ah Kim ◽  
Su-Lyun Kim
Keyword(s):  
Cytochrome P450 ◽  
Drug Interaction ◽  
Human Liver ◽  
Liver Microsomes ◽  
Inhibitory Effect ◽  
Human Liver Microsomes ◽  
Human Cytochrome ◽  
Cytochrome P450 Isoforms ◽  
Potent Inhibitory Effect ◽  
Cyp Isoforms

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.

scholarly journals Alcohol-Induced Increase in the Content of CYP2E1 in Human Liver Microsomes Causes a Multifold Activation of CYP3A4 and Attenuates its Cooperativity

2020 ◽  
Author(s):  
Bikash Dangi ◽  
Nadezhda Y. Davydova ◽  
Nikita E. Vavilov ◽  
Victor G. Zgoda ◽  
Dmitri R. Davydov
Keyword(s):  
Cytochrome P450 ◽  
Human Liver ◽  
Liver Microsomes ◽  
Alcohol Exposure ◽  
Inhibitory Effect ◽  
Human Liver Microsomes ◽  
Specific Substrate ◽  
Physiological Relevance ◽  
Physical Interactions

AbstractHere we investigate the effect of alcohol-induced increase in the content of CYP2E1 in human liver microsomes (HLM) on the function of CYP3A4. In these studies we used a model that implements enrichment of HLM samples with CYP2E1 through membrane incorporation of the purified protein. Enrichment of HLM with CYP2E1 considerably increases the rate of metabolism of 7-benzyloxyquinoline (BQ) and attenuates the homotropic cooperativity observed with this CYP3A4-specific substrate. Incorporation of CYP2E1 also eliminates the activating effect of α-Naphthoflavone (ANF) on BQ metabolism seen in some untreated HLM samples. To probe the physiological relevance of these effects we compared three pooled preparations of HLM from normal donors (HLM-N) with a preparation obtained from heavy alcohol consumers (HLM-A). The composition of the P450 pool in all four samples was characterized with mass-spectrometric determination of 11 cytochrome P450 species. The molar content of CYP2E1 in HLM-A was from 2.5 to 3.3 times higher than that found in HLM-N. In contrast, the content of CYP3A4 in HLM-A was the lowest among all four HLM samples. Despite of that, HLM-A exhibited much higher rate of metabolism and lower degree of homotropic cooperativity with BQ, similar to that observed in CYP2E1-enriched HLM-N. In order to substantiate the hypothesis on the involvement of physical interactions between CYP2E1 and CYP3A4 in the observed effects we probed hetero-association of these proteins in Supersomes™ containing recombinant CYP3A4 with a technique based on homo-FRET and employing CYP2E1 labeled with BODIPY-618 maleimide. These experiments demonstrated high affinity interactions between the two enzymes and revealed an inhibitory effect of ANF on their hetero-association. Our results demonstrate that the catalytic activity and allosteric properties of CYP3A4 are fundamentally dependent on the composition of the cytochrome P450 ensemble and imply a profound impact of chronic alcohol exposure on the pharmacokinetics of drugs metabolized by CYP3A4.

Deactivation of anti-cancer drug letrozole to a carbinol metabolite by polymorphic cytochrome P450 2A6 in human liver microsomes

Xenobiotica ◽  
2009 ◽  
Vol 00 (00) ◽  
pp. 090901052053001-8
Author(s):  
K. Murai ◽  
H. Yamazaki ◽  
K. Nakagawa ◽  
R. Kawai ◽  
T. Kamataki
Keyword(s):  
Cytochrome P450 ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Cancer Drug ◽  
Anti Cancer ◽  
Cytochrome P450 2A6

Selegiline Metabolism and Cytochrome P450 Enzymes:In vitro Study in Human Liver Microsomes*

2000 ◽  
Vol 86 (5) ◽  
pp. 215-221 ◽  
Author(s):  
Paivi Taavitsainen ◽  
Markku Anttila ◽  
Leena Nyman ◽  
Hari Karnani ◽  
Jarmo S. Salonen ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Vitro Study
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