The use of deuterium isotope effects to probe the active site properties, mechanism of cytochrome P450-catalyzed reactions, and mechanisms of metabolically dependent toxicity.

doi:10.1124/DMD.31.12.1481

Paper

The use of deuterium isotope effects to probe the active site properties, mechanism of cytochrome P450-catalyzed reactions, and mechanisms of metabolically dependent toxicity.

Published Dec 1, 2003 · S. Nelson, W. Trager

Drug metabolism and disposition: the biological fate of chemicals

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147

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6

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Abstract

Critical elements from studies that have led to our current understanding of the factors that cause the observed primary deuterium isotope effect, (kH/kD)obs, of most enzymatically mediated reactions to be much smaller than the "true" or intrinsic primary deuterium isotope effect, kH/kD, for the reaction are presented. This new understanding has provided a unique and powerful tool for probing the catalytic and active site properties of enzymes, particularly the cytochromes P450 (P450). Examples are presented that illustrate how the technique has been used to determine kH/kD, and properties such as the catalytic nature of the reactive oxenoid intermediate, prochiral selectivity, the chemical and enzymatic mechanisms of cytochrome P450-catalyzed reactions, and the relative active site size of different P450 isoforms. Examples are also presented of how deuterium isotope effects have been used to probe mechanisms of the formation of reactive metabolites that can cause toxic effects.

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Study Snapshot

Deuterium isotope effects can probe enzyme catalytic and active site properties, and help understand metabolically dependent toxicity mechanisms.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

The use of deuterium isotope effects to probe the active site properties, mechanism of cytochrome P450-catalyzed reactions, and mechanisms of metabolically dependent toxicity.

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References

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3-methylindole metabolizes to 3-methyleneindolenine, which forms adducts with various nucleosides, primarily forming dGuo, dAdo, and dCyd adducts, with less dCyd

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Sulfate conjugates of NDPS metabolites can be fast acting nephrotoxicants, potentially contributing to NDPS nephrotoxicity in vivo.

Rate-determining steps in phenacetin oxidations by human cytochrome P450 1A2 and selected mutants.

The rate-limiting steps in phenacetin oxidations by human cytochrome P450 1A2 remain relatively unchanged over an 800-fold range of catalytic activity.

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