Kinetic deuterium isotope effects for 7-alkoxycoumarin O-dealkylation reactions catalyzed by human cytochromes P450 and in liver microsomes. Rate-limiting C-H bond breaking in cytochrome P450 1A2 substrate oxidation

Kinetic carbon-13 and deuterium isotope effects are calculated for the SN2 reaction of CH3I with CN-. The normal vibrational frequencies of CH3I, the transition state I · · · CH3 · · · CN, and the corresponding isotope substituted reactants and transition states are evaluated from the force constants by solving the secular equation on an IBM 7094 computer.Values for 7 force constants of the planar CH3 moiety in the transition state (with an sp2 C atom) are obtained by comparison with suitable stable molecules. The stretching force constants related to the bonds being broken or newly formed (fCC, fCC and the interaction between these two stretches, /12) are chosen in such a way that either a zero or imaginary value for νʟ≠ will result. Agreement between calculated and experimental methyl-C13 isotope effects (k12/ k13) can be obtained only in sample calculations with sufficiently large values of f12 which lead to imaginary νʟ≠ values. Furthermore, the difference between fCI and fCC must be small (in the order of 1 mdyn/Å). The bending force constants, fHCI and fHCC, exert relatively little influence on k12/k13. They are important for the D isotope effect, however. As soon as experimental data on kH/kD are available it will be possible to derive a value for fHCC in the transition state if fHCI is kept constant at 0.205 mdynA, and if fCI, fCC and f12 are held in a reasonable order of magnitude. There is no agreement between experimental and calculated cyanide-C13 isotope effects. Possible explanations are discussed. — Since fCI and fCC cannot differ much it must be concluded that the transition state is relatively “symmetric”, with approximately equal amounts of bond making and bond breaking.

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Deuterium isotope effects in drug pharmacokinetics II: Substrate-dependence of the reaction mechanism influences outcome for cytochrome P450 cleared drugs

PLoS ONE ◽

10.1371/journal.pone.0206279 ◽

2018 ◽

Vol 13 (11) ◽

pp. e0206279 ◽

Cited By ~ 5

Author(s):

Hao Sun ◽

David W. Piotrowski ◽

Suvi T. M. Orr ◽

Joseph S. Warmus ◽

Angela C. Wolford ◽

...

Keyword(s):

Cytochrome P450 ◽

Reaction Mechanism ◽

Isotope Effects ◽

Substrate Dependence ◽

Deuterium Isotope Effects ◽

Drug Pharmacokinetics

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ChemInform Abstract: THE α- AND β-DEUTERIUM ISOTOPE EFFECTS IN THE HYDROLYSIS OF TETRAHYDRONAPHTHALENE EPOXIDES: RATE-LIMITING HYDROGEN MIGRATION IN THE SPONTANEOUS HYDROLYSIS OF 6-METHOXY-1,2,3,4-TETRAHYDRONAPHTHALENE OXIDE

Chemischer Informationsdienst ◽

10.1002/chin.198245101 ◽

1982 ◽

Vol 13 (45) ◽

Author(s):

R. E. GILLILAN ◽

T. M. POHL ◽

D. L. WHALEN

Keyword(s):

Isotope Effects ◽

Hydrogen Migration ◽

Spontaneous Hydrolysis ◽

Deuterium Isotope Effects ◽

Rate Limiting ◽

Hydrolysis Of

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Deuterium Isotope Effects as a Tool in the Study of Ethanol Oxidation in Rat Liver Microsomes

Pharmacology & Toxicology ◽

10.1111/j.1600-0773.1989.tb01125.x ◽

1989 ◽

Vol 65 (1) ◽

pp. 45-54 ◽

Cited By ~ 3

Author(s):

Frank Lundquist ◽

Lillian Lund Hansen

Keyword(s):

Rat Liver ◽

Ethanol Oxidation ◽

Isotope Effects ◽

Liver Microsomes ◽

Rat Liver Microsomes ◽

Deuterium Isotope Effects

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Characterization of O-demethylations and Aromatic Hydroxylations Mediated by Cytochromes P450 in the Metabolism of Flavonoid Aglycons

Croatica Chemica Acta ◽

10.5562/cca3528 ◽

2019 ◽

Vol 92 (1) ◽

pp. 115-123 ◽

Cited By ~ 4

Author(s):

Goran Benković ◽

Hrvoje Rimac ◽

Željan Maleš ◽

Siniša Tomić ◽

Zoran Lončar ◽

...

Keyword(s):

Cytochrome P450 ◽

Human Liver ◽

Cytochromes P450 ◽

Liver Microsomes ◽

Cytochrome P450 Enzymes ◽

Uv Detector ◽

Aromatic Hydroxylation ◽

Metabolism Of Xenobiotics ◽

Kinetics Of

One of the most important groups of metabolic enzymes is cytochrome P450 superfamily. These enzymes are important in terms of the catalytic diversity and the large number of xenobiotics that are detoxified or activated by converting to reactive metabolites. Flavonoids are xenobiotics to which humans are exposed through diet. Data on their oxidative metabolism mediated by cytochromes P450 are limited. The aim of this study was to determine the enzymatic kinetics of O-demethylation and aromatic hydroxylation of flavonoid aglycons on recombinant cytochrome P450 enzymes and human liver microsomes systems. The study was performed on ten flavonoids, namely 3,7-dihydroxyflavone, 7-hydroxyflavone, acacetin, apigenin, flavone, galangin, kaempferol, naringenin, sakuranetin, and tangeretin using liquid chromatography coupled with mass spectrometry and UV detector. Most relevant enzyme involved in metabolism of flavonoid aglycons is CYP1A2, and its catalytic effectiveness ranges from 0.5 to 2.9 × 106 M–1 min–1. Having in mind high expression and involvement of CYP1A2 in metabolism of xenobiotics including drugs, and its intraindividual differences in expression and activity, potential of drug-flavonoid competitive interactions/inhibitions should be considered when consuming dietary supplement and foods rich in flavonoids.

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