Assembling the P450 Puzzle: on the Sources of Nonadditivity in Drug Metabolism.
Trends in pharmacological sciences(2021)
摘要
There is an increasing number of indications of an oversimplification in the premise that the cumulative properties of the human drug-metabolizing ensemble represent a simple aggregate of the properties of the constituting enzymes. Recent studies of the functional effects of hetero-association of multiple cytochrome P450 species and their interactions with metabolically related enzymes revealed a tight integration in the drug-metabolizing ensemble. In our opinion, the sources of interindividual variability in drug metabolism can be elucidated only when considering this ensemble as a multienzyme system, the functional parameters of which are determined by interactions between its constituents. In this article, we present a conceptual model providing a mechanistic explanation for the functional effects of the interactions between multiple P450 species and propose a clue to understanding the nonadditive behavior of the drug-metabolizing ensemble.
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