Online citations, reference lists, and bibliographies.
← Back to Search

Differential Selectivity Of Cytochrome P450 Inhibitors Against Probe Substrates In Human And Rat Liver Microsomes.

V. Eagling, J. Tjia, D. Back
Published 1998 · Chemistry, Medicine

Save to my Library
Download PDF
Analyze on Scholarcy Visualize in Litmaps
Reduce the time it takes to create your bibliography by a factor of 10 by using the world’s favourite reference manager
Time to take this seriously.
Get Citationsy
AIMS Chemical inhibitors of cytochrome P450 (CYP) are a useful tool in defining the role of individual CYPs involved in drug metabolism. The aim of the present study was to evaluate the selectivity and rank the order of potency of a range of isoform-selective CYP inhibitors and to compare directly the effects of these inhibitors in human and rat hepatic microsomes. METHODS Four chemical inhibitors of human cytochrome P450 isoforms, furafylline (CYP1A2), sulphaphenazole (CYP2C9), diethyldithiocarbamate (CYP2E1), and ketoconazole (CYP3A4) were screened for their inhibitory specificity towards CYP-mediated reactions in both human and rat liver microsomal preparations. Phenacetin O-deethylation, tolbutamide 4-hydroxylation, chlorzoxazone 6-hydroxylation and testosterone 6beta-hydroxylation were monitored for enzyme activity. RESULTS Furafylline was a potent, selective inhibitor of phenacetin O-deethylation (CYP1A2-mediated) in human liver microsomes (IC50 = 0.48 microM), but inhibited both phenacetin O-deethylation and tolbutamide 4-hydroxylation (CYP2C9-mediated) at equimolar concentrations in rat liver microsomes (IC50 = 20.8 and 24.0 microM respectively). Sulphaphenazole demonstrated selective inhibition of tolbutamide hydroxylation in human liver microsomes but failed to inhibit this reaction in rat liver microsomes. DDC demonstrated a low level of selectivity as an inhibitory probe for chlorzoxazone 6-hydroxylation (CYP2E1-mediated). DDC also inhibited testosterone 6beta-hydroxylation (CYP3A-mediated) in man and rat, and tolbutamide 4-hydroxylase activity in rat. Ketoconazole was a very potent, selective inhibitor of CYP3A4 activity in human liver (IC50 = 0.04 microM). Although inhibiting CYP3A in rat liver it also inhibited all other reactions at concentrations < or = 5 microM. CONCLUSIONS It is evident that CYP inhibitors do not exhibit the same selectivity in human and rat liver microsomes. This is due to differential selectivity of the inhibitors and/or differences in the CYP isoform responsible for metabolism in the different species.
This paper references
Protein measurement with the Folin phenol reagent.
O. H. Lowry (1951)
Purification and characterization of liver microsomal cytochromes p-450: electrophoretic, spectral, catalytic, and immunochemical properties and inducibility of eight isozymes isolated from rats treated with phenobarbital or beta-naphthoflavone.
F. Guengerich (1982)
Regio- and stereoselective metabolism of two C19 steroids by five highly purified and reconstituted rat hepatic cytochrome P-450 isozymes.
A. Wood (1983)
Ketoconazole: a potent inhibitor of cytochrome P-450-dependent drug metabolism in rat liver.
J. Sheets (1984)
The effect of ketoconazole on hepatic oxidative drug metabolism in the rat in vivo and in vitro.
C. G. Meredith (1985)
The metabolism of 17 alpha-ethinyloestradiol by human liver microsomes: formation of catechol and chemically reactive metabolites.
H. Purba (1987)
Regulation of testosterone hydroxylation by rat liver microsomal cytochrome P-450.
A. J. Sonderfan (1987)
Constitutive testosterone 6 beta-hydroxylase in rat liver.
S. Imaoka (1988)
Human liver microsomal steroid metabolism: identification of the major microsomal steroid hormone 6 beta-hydroxylase cytochrome P-450 enzyme.
D. Waxman (1988)
In vitro inhibition studies of tolbutamide hydroxylase activity of human liver microsomes by azoles, sulphonamides and quinolines.
D. Back (1988)
Species variation in the response of the cytochrome P-450-dependent monooxygenase system to inducers and inhibitors.
A. Boobis (1990)
High affinity phenacetin O-deethylase is catalysed specifically by cytochrome P450d (P450IA2) in the liver of the rat.
D. Sesardic (1990)
Hydroxylation of chlorzoxazone as a specific probe for human liver cytochrome P-450IIE1
R. Peter (1990)
Tolbutamide hydroxylation by human, rabbit and rat liver microsomes and by purified forms of cytochrome P-450.
M. Veronese (1990)
Furafylline is a potent and selective inhibitor of cytochrome P450IA2 in man.
D. Sesardic (1990)
Tolbutamide and mephenytoin hydroxylation by human cytochrome P450s in the CYP2C subfamily.
M. Relling (1990)
Steroid hormone hydroxylase specificities of eleven cDNA-expressed human cytochrome P450s.
D. Waxman (1991)
Role of human cytochrome P-450 IIE1 in the oxidation of many low molecular weight cancer suspects.
F. Guengerich (1991)
Cytochromes P-450 in rats: structures, functions, properties and relevant human forms.
P. Souček (1992)
Effects of imidazole derivatives on cytochromes P450 from human hepatocytes in primary culture
M. Maurice (1992)
Isoform-selective mechanism-based inhibition of human cytochrome P450 1A2 by furafylline.
K. Kunze (1993)
Site-directed mutation studies of human liver cytochrome P-450 isoenzymes in the CYP2C subfamily.
M. Veronese (1993)
In vitro approaches can predict human drug metabolism.
D. J. Bickett (1993)
In vitro methods for assessing human hepatic drug metabolism: their use in drug development.
S. Wrighton (1993)
Both cytochromes P450 2E1 and 1A1 are involved in the metabolism of chlorzoxazone.
V. Carrière (1993)
Specificity of substrate and inhibitor probes for human cytochromes P450 1A1 and 1A2.
W. Tassaneeyakul (1993)
P450 in the rat and man: methods of investigation, substrate specificities and relevance to cancer.
V. Nedelcheva (1994)
Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians.
T. Shimada (1994)
Selective inhibitors of cytochromes P450.
J. Halpert (1994)
Evaluation of triacetyloleandomycin, alpha-naphthoflavone and diethyldithiocarbamate as selective chemical probes for inhibition of human cytochromes P450.
Thomas K. H. Chang (1994)
Cytochrome P-450 2E1 is not the sole catalyst of chlorzoxazone hydroxylation in rat liver microsomes. off.
Z. Jayyosi (1995)
Structural basis of selective cytochrome P450 inhibition.
J. Halpert (1995)
Cytochrome P450 inhibitors. Evaluation of specificities in the in vitrometabolism of therapeutic agents by human liver microsomes.
D. J. Newton (1995)
Review : Heterogeneity of cytochrome P450 and its toxicological significance
Alan J. Paine (1995)
Ketoconazole and sulphaphenazole as the respective selective inhibitors of P4503A and 2C9.
S. J. Baldwin (1995)
Putative active site template model for cytochrome P4502C9 (tolbutamide hydroxylase).
B. Jones (1996)
Molecular modelling of CYP1A subfamily members based on an alignment with CYP102: rationalization of CYP1A substrate specificity in terms of active site amino acid residues.
D. Lewis (1996)
Contribution of human CYP3A subfamily members to the 6-hydroxylation of chlorzoxazone.
J. C. Gorski (1997)

This paper is referenced by
Elucidation of plasma protein binding, blood partitioning, permeability, CYP phenotyping and CYP inhibition studies of Withanone using validated UPLC method: An active constituent of neuroprotective herb Ashwagandha.
Sandeep K. Singh (2021)
The methylimidazolium ionic liquid M8OI is detectable in human sera and is subject to biliary excretion in perfused human liver
Alistair C. Leitch (2021)
Evaluation of the effect of Bovis Calculus Artifactus on eight rat liver cytochrome P450 isozymes using LC-MS/MS and cocktail approach
Yun-Jing Zhang (2021)
Cytochrome P450 Inhibition by Antimicrobials and Their Mixtures in Rainbow Trout Liver Microsomes In Vitro.
T. Pihlaja (2021)
Dietary Polyphenols Inhibit the Cytochrome P450 Monooxygenase Branch of the Arachidonic Acid Cascade with Remarkable Structure-Dependent Selectivity and Potency.
N. Kampschulte (2020)
Mass spectrometric characterization of carfentanil metabolism in human, dog, and rat lung microsomes via comparison to chemically synthesized metabolite standards
Li Kong (2020)
Development of a method to determine cytochrome P450 1A2, 2C9, 2D6 and 3A4 activity sheep hepatic microsomes.
Grace M McBride (2020)
The cytochrome P450 metabolic profiling of SMU-B in vitro, a novel small molecule tyrosine kinase inhibitor.
Y. Jiang (2020)
Fe-N-C Nanozyme with Both Accelerated and Inhibited Biocatalytic Activities Capable of Accessing Drug-Drug Interaction.
Yuan Xu (2020)
Influence of a combination of triptolide and ferulic acid on the activities of CYP450 enzymes and oxidative stress in HaCaT cells
Jianlin Zhang (2020)
Differential Effects of 1α,25-Dihydroxyvitamin D3 on the Expressions and Functions of Hepatic CYP and UGT Enzymes and Its Pharmacokinetic Consequences In Vivo
Trang Nguyen Kieu Doan (2020)
Identification and characterization of the enzymes responsible for the metabolism of the non-steroidal anti-inflammatory drugs, flunixin meglumine and phenylbutazone, in horses.
H. Knych (2020)
Risk assessment of the chiral pesticide fenamiphos in a human model: Cytochrome P450 phenotyping and inhibition studies.
Nayara Cristina Perez de Albuquerque (2020)
Excretion, Metabolism and Cytochrome P450 Inhibition of Methyl 3,4-Dihydroxybenzoate (MDHB): A Potential Candidate to Treat Neurodegenerative Diseases
Jia Hui Wang (2019)
CYP3A4/5 mediates the metabolic detoxification of humantenmine, a highly toxic alkaloid from Gelsemium elegans Benth.
Rongjin Sun (2019)
Inhibition of Rat CYP1A2 and CYP2C11 by Honokiol, a Component of Traditional Chinese Medicine
J. Li (2019)
Structure-dependent hepato-cytotoxic potencies of selected pyrrolizidine alkaloids in primary rat hepatocyte culture.
Lan Gao (2019)
Human CYP3A4-mediated toxification of the pyrrolizidine alkaloid lasiocarpine.
Johanna Ebmeyer (2019)
In vitro modulation of cytochrome P450 isozymes and pharmacokinetics of caffeine by extracts of Hibiscus sabdariffa Linn calyx
Johnson Segun Showande (2019)
Kinetics of Cyclophosphamide Metabolism in Humans, Dogs, Cats, and Mice and Relationship to Cytotoxic Activity and Pharmacokinetics
D. Ramirez (2019)
Baihe Zhimu formula attenuates the efficacy of tamoxifen against breast cancer in mice through modulation of CYP450 enzymes
Hailong Li (2019)
Validation of an HPLC Method for the Simultaneous Quantification of Metabolic Reaction Products Catalysed by CYP2C11 Enzymes in Rat Liver Microsomes: In Vitro Inhibitory Effect of Salicylic Acid on CYP2C11 Enzyme
Hassan Salhab (2019)
Screening of ten cytochrome P450 enzyme activities with 12 probe substrates in human liver microsomes using cocktail incubation and liquid chromatography–tandem mass spectrometry
Hyun-Ji Kim (2019)
Application of cytochrome P450 reactivity on the characterization of chemical compounds and its association with repeated-dose toxicity.
Michiko Watanabe (2019)
Effect of Berberine on In Vitro Metabolism of Sulfonylureas: A herb-drug interactions study.
Amrinder Singh (2019)
Sensitive CometChip assay for screening potentially carcinogenic DNA adducts by trapping DNA repair intermediates
Le P. Ngo (2019)
Altered hepatic drug-metabolizing activity in rats suffering from hypoxemia with experimentally induced acute lung impairment
Y. Hori (2018)
Relative contribution of rat CYP isoforms responsible for stereoselective metabolism of carvedilol.
M. Iwaki (2018)
N‐demethylation of N‐methyl‐4‐aminoantipyrine, the main metabolite of metamizole
F. Bachmann (2018)
Effect of Naltrexone Hydrochloride on Cytochrome P450 1A2, 2C9, 2D6, and 3A4 Activity in Human Liver Microsomes
H. Alrabiah (2018)
UGT‐mediated metabolism plays a dominant role in the pharmacokinetic behavior and the disposition of morusin in vivo and in vitro
Chuqi Hou (2018)
Inhibition of cytochrome P450 enzymes by thymoquinone in human liver microsomes
A. Albassam (2018)
See more
Semantic Scholar Logo Some data provided by SemanticScholar