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The Ah receptor: binding specificity only for foreign chemicals?

D W Nebert, H J Eisen, O Hankinson

Biochemical Pharmacology

|March 15, 1984

Summary

The Ah receptor controls drug metabolism enzyme induction in mice. This process involves gene activation, mRNA production, and protein synthesis, potentially serving essential life functions.

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Area of Science:

Pharmacology and Toxicology
Molecular Biology
Genetics

Background:

The murine Ah locus regulates the induction of key drug-metabolizing enzymes, including cytochromes P450 and UDP-glucuronosyltransferase.
The Ah gene encodes a cytosolic receptor crucial for mediating these induction responses.

Purpose of the Study:

To elucidate the molecular mechanisms underlying the Ah receptor-mediated induction of drug-metabolizing enzymes.
To investigate the role of the Ah receptor in both xenobiotic metabolism and potentially endogenous physiological processes.

Main Methods:

Utilized classical pharmacologic methods, including structure-activity relationship studies.
Employed standard biochemical techniques.
Incorporated advanced methods such as recombinant DNA technology and somatic-cell genetics.

Main Results:

Detailed the multi-step induction response: chemical binding to the Ah receptor, nuclear translocation, gene binding, transcriptional activation, and protein synthesis.
Observed distinct temporal patterns in mRNA precursor and mature mRNA levels, preceding protein increases.
Highlighted the importance of membrane-bound polysomes in protein translation and subsequent enzyme activity.

Conclusions:

The Ah receptor orchestrates a complex cascade leading to enhanced drug metabolism.
Mouse models with Ah receptor defects have been instrumental in unraveling these pathways.
The Ah receptor may play a role in essential endogenous functions beyond drug metabolism.

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