Human Ah receptor (AHR) gene: localization to 7p15 and suggestive correlation of polymorphism with CYP1A1 inducibility

Distinct response to dioxin in an arylhydrocarbon receptor (AHR)-humanized mouse

“…A possible explanation of the relative resistance of the hAHR knock-in mouse to TCDD lies in the qualitative difference between the human and mouse AHR molecules. Assuming that the abundance of the hAHR protein is the same as that of the endogenous mouse AHR, our results imply that the hAHRmediated response to TCDD in vivo is much lower than that of DBA͞2 AHR, although previous reports showed that their affinities to TCDD, as measured in vitro, are almost the same (9,19). Alignment of the primary amino acid sequences of the two molecules indicates the considerable divergence in the Cterminal regions (9) and the deletion analysis differently localized the transcriptional activity within the regions (31).…”

“…EcoRI digestion generated 11.0-and 6.2-kb bands for the wild-type and targeted alleles, respectively, by using the 5Ј-genomic probe. that hAHR and DBA͞2 AHR exhibit similar dissociation constants for TCDD binding as measured in vitro (9,19). This result suggests that ligand binding does not fully define the integrated function of hAHR.…”

“…The dissociation constant (K d ) of hAHR for TCDD was comparable to that of TCDD-resistant DBA͞2 AHR (9,19), suggesting that humans might be resistant to TCDD. By contrast, high homology of the human receptor to the AHR of the guinea pig, which is the most sensitive animal to TCDD, suggests a high responsiveness of humans to the toxin (20).…”

Aromatic Hydrocarbon Receptor Polymorphism: Development of New Methods to Correlate Genotype with Phenotype

“…An A375V change has been reported to confer most of the observed phenotypic differences between B6 and D2 (15). With hepatic cytosol from B6 and D2 mice, ligand-affinity differences were found to range between 4-and 10-fold for the B6 and D2 AHRs (1618, whereas ligand-affinity differences range between 2-and 6-fold for the B6 and D2 AHRs when cDNA-expressed AHRs are studied (9,15 (15,22, …”

“…CYPlAl inducibiity varies by more than 30-fold in humans (20)(21)(22)(23), and Scatchard plot analyses of 106 human placental samples have shown a >35-fold difference in AHR affinity between the highest and lowest phenotype (24,25), yet there has not been any direct correlation established between the degree of CYPlA1 inducibility and the variation in AHR affinity in humans nucleotide or amino acid change in the human AHR has been unequivocally associated with ligand variability. Substitution of alanine for valine at position 381 (equivalent to position 375 in the mouse) was shown to increase ligand affinity several-fold in an in vitro cDNA-expression binding assay (15); however, the human AHR protein from the HepG2 and A431 cell lines, as well as from at least eight individuals, contains valine at position 381 in all cases (15,22,26- (Fig.…”