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.

Figure 1

A schematic illustration of the three theoretical elements (see text) that govern the selective chemical induction of CYP isoforms. Inset A depicts a mediating receptor that has an inducer-binding site and a highly selective xenobiotic response element (XRE)-binding site. Inset B depicts a CYP isoform with a substrate-binding site that is identical (or highly similar) in steric structure to the inducer-binding site of its corresponding receptor.

Figure 2

Some deducible pharmacological characteristics that are associated with the hypothesis that each chemically-inducible CYP isoform is mediated by a corresponding receptor. The upper panels (A, B, C) depict a possible situation where an inducer chemical (I) can bind and then activate a number of structurally-similar receptors (R₁, R₂, R₃) with different binding affinities. The induction potency of a chemical for a given CYP isoform will largely depend on its binding affinity for its mediating receptor. As depicted, the binding affinity of inducer I for R₁, R₂, and R₃ is assumed to follow the rank order of R₁ > R₂ > R₃. It is expected that inducer I is a more potent inducer for the induction of R₁-mediated CYP isoform than R₂- or R₃-mediated CYP isoforms. In comparison, the maximal induction of a given isoform (achieved at high inducer concentrations) may be, in a significant part, determined by the levels of the inducer receptor present. Note that in this hypothetical case since the receptors R₁, R₂, and R₃ bind to the same chemical moiety of the inducer, it is expected that the induced CYP isoforms will also have the ability to catalyze the same metabolic reaction (albeit they may have rather different K_M values). The middle panels (D, E, F) depict a situation where multiple chemical moieties of the same inducer chemical may interact with different inducer receptors. The binding affinity of each moiety for the corresponding receptor will basically determine the relative potency of induction of a corresponding CYP isoform, and the total receptor levels may, in part, determine the magnitude of induction of a given CYP isoform. There is considerable experimental evidence showing that a chemical inducer (such as phenobarbital) can induce multiple CYP isoforms with widely different potencies and efficacies. Notably, since in this case different moieties of the inducer chemical interact with different receptors to induce different CYP isoforms, it is expected that each of the induced CYP isoforms will also have a preferential ability to metabolize the corresponding moiety of the inducer chemical. The bottom panels (G, H, I) depict a situation where an inducer chemical may activate multiple inducer receptors (such as R₁ and R₂), resulting in the induction of corresponding CYP isoforms, but it may also competitively block some other inducer receptors (such as R₃), resulting in a reduced expression of the corresponding CYP isoform. This phenomenon has been observed with some inducer chemicals, such as phenobarbital.