The Ah receptor: binding specificity only for foreign chemicals?

The murine Ah locus controls the induction of at least four drug-metabolizing enzymes: cytochromes P1-450, P2-450, and P3-450, and UDP-glucuronosyltransferase. The Ah gene codes for a cytosolic receptor. It is known that the induction response includes: (i) high-affinity binding of specific foreign chemicals to the Ah receptor; (ii) temperature-dependent translocation of the "activated" inducer-receptor complex into the nucleus; (iii) binding of the complex presumably to chromatin components; (iv) transcriptional activation of specific genes; (v) maximal increases in intranuclear high-molecular-weight precursor mRNA (pre-mRNA) that precede by several hours the maximal increases in cytoplasmic mRNA; (vi) translation of the mRNA principally on membrane-bound polysomes; and (vii) increases in the specific membrane-bound proteins (including architectural arrangement with other membrane-bound moieties) that reflect enhanced specific drug-metabolizing activities. It is not known how many of the other drug metabolism induction responses are also governed by receptors. The Ah locus studies have been chiefly unraveled in the mouse, due to several inbred strains having a receptor defect. In addition to "classical" pharmacologic methods (such as structure-activity studies) and standard biochemical techniques, the newer methods of recombinant DNA technology and somatic-cell genetics in culture are shown to be important in understanding the Ah receptor and its induction response. It is possible that this receptor is required for endogenous functions critical to life processes, as well as its function in the induction of drug metabolism by certain polycyclic aromatic compounds.