On the general mechanism of selective induction of cytochrome P450 enzymes by chemicals: some theoretical considerations

Abstract

Importance of the field: The CYP isoforms that are selectively induced following exposure to structurally-diverse chemicals often are the ones capable of metabolizing these chemicals. However, the molecular mechanism underlying this apparent functional coupling is not understood at present.

Areas covered in this review: Three hypotheses are developed to explain the complex process of selective chemical induction of CYPs: i) each inducible CYP may have a corresponding intracellular receptor that interacts with the inducer chemical and mediates the selective induction of this CYP; ii) each inducible CYP and its corresponding receptor may share highly similar steric structures for their substrate/inducer-binding sites and iii) each chemically-inducible CYP gene may have distinct genomic response element(s) that interact selectively with the corresponding receptor.

What the reader will gain: The readers are introduced to a novel theoretical framework that offers a plausible mechanistic explanation at the molecular level concerning the complex process of how an organism selectively activates the biosynthesis of certain CYP isoform(s) that can effectively metabolize a chemical to which the organism is exposed.

Take home message: The theoretical framework developed herein seeks to ignite additional critical thinking on this important research subject as well as to promote experimental testing of the proposed theories in the future. Undoubtedly, these studies will enhance the understanding of the molecular mechanisms for the selective induction of CYP enzymes by chemicals.

Keywords::

• Ah receptor
• chemical inducers
• CYP isoform
• mechanism of enzyme induction
• nuclear receptors
• selective enzyme induction

Acknowledgements

When an earlier version of this manuscript (containing the same three theoretical elements) was completed in the Fall of 1996, AH Conney at Rutgers University (Piscataway, NJ, USA) gave the manuscript a careful reading and offered encouragement as well as some additional literature examples for consideration. The author thanks AH Conney for his encouragement and generous help. The author also wishes to express his indebtedness to many researchers in this research field whose equally important research work has been left out of the reference list solely because of space constraint. Finally, the author thanks SC Bishop for proof reading of the manuscript, and Expert Opinion on Drug Metabolism & Toxicology for providing a rare forum for this theoretical/opinion piece, which otherwise may never see the light of the day.

Notes

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