Human Ah receptor (AHR) gene: localization to 7p15 and suggestive correlation of polymorphism with CYP1A1 inducibility.
The mammalian aromatic hydrocarbon receptor (AHR) is a ubiquitous ligand-activated transcription factor. AHR ligands include 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin), benzo[a]pyrene, and polychlorinated and polybrominated biphenyls; the endogenous ligand is not yet known. Following ligand binding, the AHR transcriptionally activates genes encoding drug-metabolizing enzymes important in both the metabolic potentiation of substrates to genotoxic reactive intermediates and ultimate carcinogens, and the detoxification of toxic or carcinogenic drugs and other environmental pollutants. AHR-mediated gene expression is also involved in many critical life processes (e.g. cell type-specific differentiation, cell division, apoptosis) by signal transduction mechanisms. Similar to mice, human populations exhibit a > 20-fold range of the CYP1A1 inducibility/AHR affinity phenotype. In the present study, we localized the human AHR gene to chromosome 7p15, using fluorescence in situ hybridization (FISH). Performing linkage analysis in a three-generation family, we show with good probability that the high CYP1A1 inducibility phenotype segregates with the 7p15 region. Sequencing 93 nt (31 amino acids) of the human AHR gene's exon 9, which is the region correlated with the mouse A375V polymorphism responsible for the major portion of high vs low CYP1A1 inducibility/AHR affinity, we found no nucleotide differences; Val-381 was present in all five individuals examined (four related and one unrelated), two of whom show "high' and three of whom show "low' CYP1A1 inducibility. These data indicate that the "high' and "low' CYP1A1 inducibility trait, in the population studied, cannot be explained by a difference among these 31 amino acids in exon 9 of the AHR gene.
Micka
J
J
Physician Scientist Training Program, CHRF, Cincinnati, OH 45229, USA.
Milatovich
A
A
Menon
A
A
Grabowski
G A
GA
Puga
A
A
Nebert
D W
DW
D000595:Amino Acid Sequence; D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008126:Lod Score; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*
D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1