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Assembling the P450 puzzle: on the sources of nonadditivity in drug metabolism.

ABSTRACT: 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.

SUBMITTER: Davydov DR

PROVIDER: S-EPMC8595691 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Assembling the P450 puzzle: on the sources of nonadditivity in drug metabolism.

Davydov Dmitri R DR Prasad Bhagwat B

Trends in pharmacological sciences 20210930 12

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 ...[more]

PMID: 34602306

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