See Aryl hydrocarbon receptor

Both a and P subunits of HIF are basic helix-loop-helix PAS proteins (bHLH-PAS) (6, 7), as observed in other transcription-factor proteins (Fig. 2). The short, basic region of bHLH-PAS proteins is directly responsible for DNA binding, and the adjacent helix-loop-helix domain allows dimerization of the two HIF subunits after translocation of HIF-a to the nucleus. The PAS domain [PAS-A/PAS-B/PAC PAS PER (periodic circadian protein), aryl hydrocarbon receptor nuclear translocator (ARNT), single-minded protein (SIM) (7) PAC motif C-terminal to PAS motifs) is involved in more specific interactions between the two subunits (for review see Reference 8). It is proposed that the specific interaction between the HIF-a and HIF-P subunits promotes folding and dimerization of the bHLH region that enables subsequent DNA binding (8). HIF-a is a Class 1 bHLH-PAS protein, which means that it can homodimer-ize and heterodimerize HIF-3 (also known as ARNT, which is... 

The acute toxicity exerted by PCBs is generally low. The most prominent effect is the pronounced induction of the MFO system in different tissues, with increased de novo synthesis and increased levels in several cytP450 isozymes. The PCBs in the environment occur as a mixture of congeners and every congener exerts specific toxicity, with some PCBs exerting exclusive effects. One such effect is the capability for planar PCBs to bind to and stimulate the cytoplasmatic aryl hydrocarbon receptor in the cell, the same receptor that is stimulated by the highly toxic polychlorinated dibenzodioxins (PCDDs) (see below). 

ClPAHs may be toxic to humans, and they have an equally important impact on the environment because several ClPAHs have also been found to exhibit mutagenic activity in Salmonella typhimurium in the Ames assay [229], To comprehensively estimate reactivity-activity for representative ClPAHs (see Fig. 6) on human and environmental species, Table 5 presents the ethoxyresorufin-O-deethylase (EROD) activities for binding substrates of chlorinated polycyclic aromatic hydrocarbons (ClPAHs) with aryl hydrocarbon receptors (AhRs) in the cytochrome... 

Dioxin, PCB, DDT, and the like, i.e., chlorinated aromatic hydrocarbons are believed to bind to a special receptor called AH receptor (AH stands for aryl hydrocarbon). The AH receptor bound with dioxin (or PCB) enters into the nucleus of the cell, and binds to a specific site of a DNA. One of the effects caused by such a binding seems to be an induction of an enzyme dependent on cytochrome P-450. Cytochrome P-450-dependent monooxygenase was talked about in Sect. 6.2.2, and is involved in the metabolism of a wide variety of compounds including steroids and foreign substances (drugs). Probably the P-450 enzymes induced by dioxin, PCB, and others would then metabolize steroid hormones unnecessarily, and thus disrupt the endocrine system. The details are still not very well understood. However, you see that the processes are all chemical reactions at the deepest level. 

Table 10-6 represents a summary of empirically arrived at structure-activity relationships, The exception of para-aryl substitutions for cardioselective P-blockers (IIB 1 and 4) should be noted but cannot be satisfactorily explained. In fact, not all the para substituents are as lipophilic as the amide ones in practolol, acebutolol (No. 11), atenolol (No. 12), or the ester group in esmolol (No. 14). The methoxyethyl group of metoprolol (No. 15) and the large hydrocarbon nature of the cyclopropylmethoxyethyl function of betaxolol (No. 13) would hardly be expected to increase aqueous solubility of these compounds (see Table 10-4). Still, all the -selective compounds are much less lipophilic than propranolol. Such apparent data correlations may have contributed to a belief that a cardioselectivity-hydrophilicity relationship exists due to some putative hydrophilic site on the Pj receptor. This notion, however, was dispelled by a study comparing hydrophilicity, substituent positions, and cardioselectivity in three sets of l-(2-propylamino)-3-phenoxy-2-propanols. The data clearly show that for each set of compounds even with identical lipophilicities (log P) the Pi-activity resided primarily in the para isomer.

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