title: Human aryl hydrocarbon receptor polymorphisms that result in loss of CYP1A1 induction.
abstract: The aryl hydrocarbon receptor (AHR) binds xenobiotic chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and regulates transcription of the P4501 subfamily that metabolizes many carcinogens. In humans, the most frequent polymorphism is R554L. We report here an additional two polymorphisms in AHR that show apparent linkage disequilibrium with the codon 554 polymorphism: the first is a previously described polymorphism, V570I; the second is a novel human AHR polymorphism, P571S. In vitro expression of these variant forms showed normal ligand binding and DNA binding activities. However, transient expression experiments revealed that the combined Ile(570) + Lys(554) variant failed to support TCDD-dependent induction of CYP1A1 expression. It is possible that the abrogation of CYP1A1 induction in the combined Lys(554) + Ile(570) variant may reduce susceptibility of the host to the carcinogenic effects of polycyclic aromatic hydrocarbons. This combination of variant genotypes is rare and appears to be confined primarily to persons of African descent.
authors.affiliation: Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: J M
authors.initials: JM
authors.lastname: Wong
authors.forename: A B
authors.initials: AB
authors.lastname: Okey
authors.forename: P A
authors.initials: PA
authors.lastname: Harper
mesh_terms: D000483:Alleles; D002460:Cell Line; D003062:Codon / Q000235:genetics; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D024202:Electrophoretic Mobility Shift Assay; D004790:Enzyme Induction / Q000235:genetics; D005006:Ethnicity / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics; D008040:Genetic Linkage / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011110:Polymorphism, Genetic / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044469:Racial Groups / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
chemical_list: D003062:Codon; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D004247:DNA; D019363:Cytochrome P-450 CYP1A1