Disease relevance of AHRR

• CONCLUSION(S): The Pro185Ala polymorphism in AHRR may constitute a susceptibility locus for dioxin-related male infertility [1].
• Human arylhydrocarbon receptor repressor (AHRR) gene: genomic structure and analysis of polymorphism in endometriosis [2].
• METHODS: The structure of the AhRR gene was reconstituted, then the genetic polymorphisms of this gene including the promoter were investigated and the link between these polymorphisms, CYP1A1 inducibility and lung cancer incidence in a French population was examined [3].
• Both cell lines demonstrated polycyclic aromatic hydrocarbon (PAH)-induced AHH activity; however, assay conditions for induction were different than those established for the control mouse hepatoma cell line, Hepa c1-9 [4].
• AhRR mRNA was also detected in various human tissue-derived cell lines, HepG2 (hepatocellular carcinoma), MCF-7 (breast carcinoma), LS-180 (colon carcinoma), ACHN (renal carcinoma), A549 (lung carcinoma), HT-1197 (bladder carcinoma), HeLa (cervix of uterus adenocarcinoma), NEC14 (testis embryonal carcinoma), and OMC-3 (ovarian carcinoma) [5].
• Further, downregulation of AHRR expression in the human lung cancer cell line conferred resistance to apoptotic signals and enhanced motility and invasion in vitro and angiogenic potential in vivo [6].

Psychiatry related information on AHRR

• Placental AHH activity did not show any relation to the age, nutritional and dietary habits, factors of indoor pollution, duration of pregnancy, nor did the weight, length and Apgar score of the babies [7].

High impact information on AHRR

• However, the predictive value of AHH activity in human or murine tissues, assayed as benzo(a)pyrene hydroxylation, as an index of individual susceptibility to mutagens and carcinogens, remains unclear because of apparent inconsistencies between results obtained from different in vitro and in vivo systems [8].
• To determine the relationship of metabolic potential to an easily quantified, short-term in vivo end point of genetic damage, we compared the ability of AHH inducible and uninducible mice to metabolize a procarcinogen, benzo(a)pyrene (BP), with the in vivo induction by BP of sister chromatid exchanges (SCEs) [8].
• The inducibility of aryl hydrocarbon hydroxylase (AHH) in human bronchial epithelium and blood monocyte was studied in 11 immediate autopsy patients without lung cancer [9].
• Induction of AHH in monocytes ranged from 1.5- to 30-fold above that of controls when the cells were exposed to 2 microgram of BA/ml medium in culture [9].
• 7. Control AHH and BA-induced AHH in bronchus were both inhibited by 100 microM 7,8-benzoflavone in vitro [9].

Chemical compound and disease context of AHRR

• The structure-dependent induction of aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase by 2,3,7,8-tetrachlorodibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzofuran, and 1,2,4,7,8-pentachlorodibenzo-p-dioxin was determined in the MCF-7, T47-D, and MDA-MB-231 human breast cancer cell lines [10].
• These three congeners and a fourth PCB, namely 3,4,4',5-tetrachlorobiphenyl, are approximate isostereomers of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and, in common with TCDD, induce hepatic microsomal benzo[a]pyrene or aryl hydrocarbon hydroxylase (AHH) in rats and rat hepatoma cells in culture [11].
• The inflammatory dose-response to topical anthralin and whole skin aryl hydrocarbon hydroxylase (AHH) activity were measured before and 24 h after application of a coal tar solution to the uninvolved skin of patients with psoriasis [12].
• The activity of aryl hydrocarbon hydroxylase (AHH) in monocytes from 13 healthy control subjects and in 16 patients with discoid psoriasis was measured [13].
• Since in twelve of the patients the psoriasis had always been localized to the palms and soles, the decreased basal and induced AHH activity appears to be a primary characteristic of psoriatic skin; AHH activity initiate an increase in epidermal cell turnover through modulation of prostaglandin and adenylate cyclase activity [14].

Biological context of AHRR

• By contrast, although the difference in the allele frequency of the AHRR polymorphism did not reach a significant level, the genotype frequency was statistically significantly different between the two groups of men [1].
• We investigated AHRR structure, function, evolution, and regulation in zebrafish, a powerful model in developmental biology and toxicology [15].
• We attempt to characterize the human AHRR gene and investigate the relationship between AHRR polymorphisms and the incidence of micropenis, a phenotype of undermasculinization [16].
• Analysis of the genomic organization of AHRR revealed an open reading frame consisting of a 2094-bp mRNA encoded by ten exons [2].
• RESULTS: The deduced sequence for human AHRR (715 residues) and the mouse AHRR protein exhibited 81% sequence homology to each other [16].

Anatomical context of AHRR

• The levels of AhRR expression were extremely high in testis, very high in lung, ovary, spleen and pancreas from adults, whereas those were low in those from fetuses [17].
• Comparison of the basal expression levels of these genes in MNCs demonstrated that MNCs from umbilical cord blood showed higher AhRR or CYP1A1 expression than those from adults [17].
• We found, however, that this germ line polymorphism of the Ahr gene did not show a significant association with aryl hydrocarbon hydroxylase (AHH) inducibility nor with lung cancer incidence [18].
• AhRR mRNA was detected in liver, breast, colon, kidney, lung, bladder, uterus, testis, ovary, and adrenal gland [5].
• Since the expression level of AhRR mRNA was prominently high in HeLa cells, it is suggested that the high expression level of AhRR might work as a negative factor for the low inducibility of the CYP1 family in HeLa cells [5].

Associations of AHRR with chemical compounds

• It appears that the negative feedback effect of AHRR on dioxin-related signaling is weaker for the proline allele than for the alanine allele, and that the hypomorphic function of the proline allele exerts a recessive adverse effect on male fertility [1].
• We found one novel polymorphism, a substitution of Ala by Pro at codon 185 (GCC to CCC), in exon 5 of the AHRR gene; among 108 healthy unrelated Japanese women, genotypes Ala/Ala, Ala/Pro, and Pro/Pro were represented, respectively, by 20 (18.5%), 49 (45.4%), and 39 (36.1%) individuals [2].
• Association of micropenis with Pro185Ala polymorphism of the gene for aryl hydrocarbon receptor repressor involved in dioxin signaling [19].
• 1. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was an inducer of microsomal benzo[alpha]pyrene hydroxylase (AHH) and 7-ethoxyresorufin O-deethylase (EROD) in MT-4 human lymphoid cell culture [20].
• Characterization of the aryl hydrocarbon receptor repressor and a comparison of its expression in Atlantic tomcod from resistant and sensitive populations [21].

Physical interactions of AHRR

• This group of PCBs exhibits many of the properties of 2,3,7,8-TCDD and related polychlorinated dibenzo-p-dioxins; there is a close parallel in the relative potencies of these PCBs for AHH induction and their binding affinities for the Ah receptor protein and some of these PCBs are also toxic [11].

Regulatory relationships of AHRR

• Thus, zebrafish possess duplicate AHR-regulated AHRR paralogs that act in a negative feedback loop to repress the AHR signaling pathway [15].

Other interactions of AHRR

• Duplicate aryl hydrocarbon receptor repressor genes (ahrr1 and ahrr2) in the zebrafish Danio rerio: structure, function, evolution, and AHR-dependent regulation in vivo [15].
• Despite the discrepancy between protein blotting and immunoinhibition data all other findings support the conclusion that maternal cigarette smoking induces the expression of the CYPIA1 gene (and not CYPIA2), resulting in an increased synthesis of P-450IA1 protein and increased AHH, ERDE and ECDE activities in human placenta [22].

Analytical, diagnostic and therapeutic context of AHRR

• Southern analyses of genomic DNA from individuals with high and low induced AHH activity demonstrated no detectable differences in the pattern or intensity of restriction fragments after treatment with benzanthracene from either individual [23].
• As those factors may affect the AHH activity, a careful control of those factors to AHH activity is necessary in epidemiological studies on the association between AHH inducibility in human lymphocytes and lung cancer [24].
• A good correlation (r = 0.79) was found between known AHH inducibility ratios for the donors, as determined by the conventional fluorometric AHH assay, and induction of BP phenol production quantitated from HPLC data [25].
• Since several drugs used in cancer treatment are substrates for polysubstrate monoxygenases, high levels of AHH activity in some human tumors may play a role in their response to chemotherapy [26].
• No relationship was observed between AHH/cytochrome c activity and age of patient, numbers of cigarettes smoked, family history of cancer, location or histological type of tumor, or level of phytohemagglutinin blastogenesis ([3H]thymidine cpm/cytochrome c) [27].

References