13C-caffeine breath test results show high dependence of aryl-hydrocarbon receptor SNPs

2020 ◽  
Author(s):  
Mchiko Ishii ◽  
Yukimoto Ishii ◽  
Tomohisa Nakayama ◽  
Yasuo Takahashi ◽  
Satoshi Asai
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Breath Test ◽  
Smoking Status ◽  
Area Under The Curve ◽  
Black Tea ◽  
Nucleotide Polymorphisms ◽  
Aryl Hydrocarbon ◽  
Significant Difference ◽  
Caffeine Metabolism ◽  
Characteristic Area

Abstract Aim: We investigated the relationship between trimethyl-13C-caffeine breath test (triCBT) and single nucleotide polymorphisms (SNPs) that are related to caffeine metabolism and consumption.Methods: Subjects were 132 young healthy adults (median 21 years: 101 male, 31 female). Subjects completed a questionnaire that enquired about their smoking status, consumption of caffeinated drinks (including coffee, black tea, green tea), height, weight, and body mass index (BMI). DNA was extracted from saliva, and genotyping was performed using TaqMan® SNP Genotyping for cytochrome P4501A2 rs762551, rs2472297, and aryl-hydrocarbon receptor rs4410790. Trimethyl 13C-caffeine (100 mg) was dissolved in distilled water and administered orally. Subsequently, breath samples were collected every 10 mins for 90 mins. Infrared spectroscopy was used to analyze the amount of 13CO2 in the expired breath, and the sum (Δ13CO2) over 90 min (S90m) was calculated.Results: All subjects had genotype CC for rs2472297. S90m was not significantly different among rs762551 genotypes; however, there was a significant difference in S90m among rs4410790 genotypes. Δ13CO2 was significantly affected by rs4410790 SNPs and smoking. The receiver operating characteristic area under the curve was 0.758 when rs4410790 phenotype C was considered positive. When the cutoff value was set to S90m (23.4 ‰), the sensitivity and specificity were 71.4% and 72.1%, respectively.Conclusions: Our results suggest that caffeine demethylation is affected by rs4410790 SNPs and smoking, and that triCBT can be used to identify SNPs in rs4410790.

Genoset for CALCA and RAMP1 Single Nucleotide Polymorphisms Are Related to the Magnitude of Headache Symptoms After Concussion: A Preliminary Observation

Neurology ◽  
2021 ◽  
Vol 98 (1 Supplement 1) ◽  
pp. S22.3-S23
Author(s):  
Michael F. La Fountaine ◽  
Anthony Testa
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Saliva Sample ◽  
Area Under The Curve ◽  
Nucleotide Polymorphisms ◽  
Blurred Vision ◽  
Single Nucleotide ◽  
Commercial Laboratory ◽  
Pain Transmission ◽  
Significant Difference ◽  
A Prospective Study

ObjectiveDetermine whether single nucleotide polymorphisms (SNPs) of the calcitonin gene-related polypeptide (CGRP)-alpha (CALCA) and the receptor activity modifying protein-1 (RAMP1) are related to headache burden during the first week after concussion.BackgroundPost-traumatic headache is a commonly reported symptom after concussion. SNPs related to CGRP are involved in the pathogenesis of migraine headaches and contribute to pain transmission and neurogenic inflammation. It is unclear in concussed persons if the headache burden is associated with genetic variations related to CGRP.Design/MethodsA prospective study was performed in 34 concussed athletes (gender: 23 female, 11 male; age: 20 ± 1 years; height: 1.75 ± 0.12 meters; weight: 73 ± 14 kilograms). Participants completed the symptom evaluation checklist from the SCAT3 within 48 hours of injury (V1), and 4 (V2) and 7 (V3) days after injury. For each visit, the self-reported score (0–6) for headache, pressure in head, blurred vision, and sensitivity to light/noise were summed. The area under-the-curve (AUC) was computed for the early (EHB: V1 to V2) and late (LHB: V2 to V3) burden of headache-related symptoms. A saliva sample was obtained and a commercial laboratory identified the genotype for CALCA (rs3781719) and RAMP1 (rs10185142) using PMR-array. RAMP1 genotypes RAMP1 (TT, TC, CC) and CALCA (AA, AG, GG) genotypes were dichotomized (T+, T−, and A+, A− respectively) and concatenated (T + A+, T + A−, T−A+, T-A−) for analyses.ResultsA significant difference for EHB (p = 0.003, partial η2 = 0.417) was present across RAMP1+CALCA genotypes, but not for the LHB. The T + A+ subgroup had a significantly elevated EHB compared to the all-other subgroups (p < 0.05: T + A + [n = 16]: 31.6 ± 2.6; T + A − [n = 9]: 17.7 ± 3.6; T−A+ [n = 8]: 18.4 ± 3.7; T−A-[n = 1]: 0.0 ± 0.0). Gender served as a covariate and diagnosed concussion history had no impact.ConclusionsThe current analysis provides a proof-of-concept to suggest that the combined T + A+ genoset from RAMP1+CALCA are associated with a greater headache burden in the first 4 days after concussion injury.

13C-caffeine breath test identifies single nucleotide polymorphisms associated with caffeine metabolism

2020 ◽  
Vol 35 (3) ◽  
pp. 321-328 ◽  
Author(s):  
Michiko Ishii ◽  
Yukimoto Ishii ◽  
Tomohiro Nakayama ◽  
Yasuo Takahashi ◽  
Satoshi Asai
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Breath Test ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Caffeine Metabolism

scholarly journals The Role of the Aryl Hydrocarbon Receptor (AHR) in Immune and Inflammatory Diseases

2018 ◽  
Vol 19 (12) ◽  
pp. 3851 ◽  
Author(s):  
Drew Neavin ◽  
Duan Liu ◽  
Balmiki Ray ◽  
Richard Weinshilboum
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Nuclear Receptor ◽  
Binding Sites ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Dependent Manner ◽  
Nucleotide Polymorphisms ◽  
Aryl Hydrocarbon ◽  
Inflammatory Processes ◽  
Targeted Gene Expression

The aryl hydrocarbon receptor (AHR) is a nuclear receptor that modulates the response to environmental stimuli. It was recognized historically for its role in toxicology but, in recent decades, it has been increasingly recognized as an important modulator of disease—especially for its role in modulating immune and inflammatory responses. AHR has been implicated in many diseases that are driven by immune/inflammatory processes, including major depressive disorder, multiple sclerosis, rheumatoid arthritis, asthma, and allergic responses, among others. The mechanisms by which AHR has been suggested to impact immune/inflammatory diseases include targeted gene expression and altered immune differentiation. It has been suggested that single nucleotide polymorphisms (SNPs) that are near AHR-regulated genes may contribute to AHR-dependent disease mechanisms/pathways. Further, we have found that SNPs that are outside of nuclear receptor binding sites (i.e., outside of AHR response elements (AHREs)) may contribute to AHR-dependent gene regulation in a SNP- and ligand-dependent manner. This review will discuss the evidence and mechanisms of AHR contributions to immune/inflammatory diseases and will consider the possibility that SNPs that are outside of AHR binding sites might contribute to AHR ligand-dependent inter-individual variation in disease pathophysiology and response to pharmacotherapeutics.

scholarly journals Gene Polymorphisms, Activation of the Aryl Hydrocarbon Receptor, and DNA Damage: A Preliminary Investigation

2018 ◽  
Author(s):  
Shadi Amini Nia ◽  
Giannina Satta ◽  
Grazianna Intranuovo ◽  
Sonia Sanna ◽  
Mariagrazia Zucca ◽  
...  
Keyword(s):  
Dna Damage ◽  
Aryl Hydrocarbon Receptor ◽  
Gene Polymorphisms ◽  
Preliminary Investigation ◽  
The Other ◽  
Luciferase Assay ◽  
Nucleotide Polymorphisms ◽  
Aryl Hydrocarbon ◽  
Non Hodgkin Lymphoma ◽  
Study Population

1) Background: We tested whether AHR activation induces DNA damage, whether polymorphisms in genes related to risk of Non-Hodgkin lymphoma are associated with DNA damage, and whether the two conditions do interact with each other. 2) Methods: Our study population included 36 subjects, randomly selected among the population controls participating in a case-control study on lymphoma in Sardinia, Italy, who donated a blood sample. We investigated 47 single nucleotide polymorphisms (SNPs) previously reported to convey risk of lymphoma; the Dual-Glo&reg; Luciferase Assay System to detect activation of the aryl hydrocarbon receptor (AhR) by the serum of study subjects; and the COMET Assay to detect DNA damage. 3) Results: Activation of the aryl hydrocarbon receptor did not increase DNA damage in our study population. On the other hand, the mutant allele (G) of rs1056932/BCL6 increased the occurrence of DNA damage (p = 0.045); such association was confirmed among AhR negative, but not AhR positive subjects. 4) Conclusions: We observed excess DNA damage associated with a gene polymorphism, namely rs1056932/ BCL6, previously reported in association with risk of lymphoma. No increase in DNA damage was associated with AhR activation per se, nor with the other gene polymorphisms we investigated.

scholarly journals Vitamin B12 and folic acid alleviate symptoms of nutritional deficiency by antagonizing aryl hydrocarbon receptor

2020 ◽  
Vol 117 (27) ◽  
pp. 15837-15845 ◽  
Author(s):  
Daniel J. Kim ◽  
Arvind Venkataraman ◽  
Priyanka Caroline Jain ◽  
Eleanor P. Wiesler ◽  
Melody DeBlasio ◽  
...  
Keyword(s):  
Folic Acid ◽  
Vitamin B12 ◽  
Aryl Hydrocarbon Receptor ◽  
Birth Defects ◽  
Target Genes ◽  
De Novo ◽  
Human Cancer ◽  
Erythroid Progenitors ◽  
Aryl Hydrocarbon ◽  
Significant Difference

Despite broad appreciation of their clinical utility, it has been unclear how vitamin B12 and folic acid (FA) function at the molecular level to directly prevent their hallmark symptoms of deficiency like anemia or birth defects. To this point, B12 and FA have largely been studied as cofactors for enzymes in the one-carbon (1C) cycle in facilitating the de novo generation of nucleotides and methylation of DNA and protein. Here, we report that B12 and FA function as natural antagonists of aryl hydrocarbon receptor (AhR). Our studies indicate that B12 and FA bind AhR directly as competitive antagonists, blocking AhR nuclear localization, XRE binding, and target gene induction mediated by AhR agonists like 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and 6-formylindolo[3,2-b]carbazole (FICZ). In mice, TCDD treatment replicated many of the hallmark symptoms of B12/FA deficiency and cotreatment with aryl hydrocarbon portions of B12/FA rescued mice from these toxic effects. Moreover, we found that B12/FA deficiency in mice induces AhR transcriptional activity and accumulation of erythroid progenitors and that it may do so in an AhR-dependent fashion. Consistent with these results, we observed that human cancer samples with deficient B12/FA uptake demonstrated higher transcription of AhR target genes and lower transcription of pathways implicated in birth defects. In contrast, there was no significant difference observed between samples with mutated and intact 1C cycle proteins. Thus, we propose a model in which B12 and FA blunt the effect of natural AhR agonists at baseline to prevent the symptoms that arise with AhR overactivation.

scholarly journals An androgen-independent mechanism underlying the androgenic effects of 3-methylcholanthrene, a potent aryl hydrocarbon receptor agonist

2020 ◽  
Vol 9 (3) ◽  
pp. 271-282
Author(s):  
Noriko Sanada ◽  
Yuka Gotoh-Kinoshita ◽  
Naoya Yamashita ◽  
Ryoichi Kizu
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Regulatory Region ◽  
Specific Inhibitor ◽  
Proximal Promoter ◽  
Luciferase Reporter ◽  
Distal Enhancer ◽  
Aryl Hydrocarbon ◽  
Aryl Hydrocarbon Receptor Agonist ◽  
Significant Difference ◽  
Androgen Independent

Abstract Aryl hydrocarbon receptor (AhR) and androgen receptor (AR) are ligand-activated transcription factors with profound cross-talk between their signal transduction pathways. Previous studies have shown that AhR agonists activate the transcription of AR-regulated genes in an androgen-independent manner; however, the underlying mechanism remains unclear. To decipher this mechanism, we evaluated the effects of 3-methylcholanthrene (3MC), a potent AhR agonist, on the transcription of AR-regulated genes in three AR-expressing cell lines. 3MC induced the expression of not only three representative AR-regulated chromosomal genes but also the exogenous AR-responsive luciferase reporter gene. No significant difference in the 3MC-induced luciferase activity was detected in the presence of SKF-525A, a non-specific inhibitor of CYP enzymes. The androgenic effects of 3MC were diminished by AhR and AR knockdown. Following 3MC treatment, the amount of nuclear AhR and AR increased synchronously. Co-immunoprecipitation revealed that AhR and AR formed a complex in the nucleus of cells treated with 3MC. AR was recruited to the proximal promoter and distal enhancer regions of the PSA gene upon the addition of 3MC. We propose that AhR activated by 3MC forms a complex with unliganded AR which translocates from the cytoplasm to the nucleus. Nuclear AR now binds the transcriptional regulatory region of AR-regulated genes and activates the transcription.

scholarly journals Circulating aryl hydrocarbon receptor-interacting protein (AIP) is independent of GH secretion

2019 ◽  
Vol 8 (4) ◽  
pp. 326-337 ◽  
Author(s):  
Marko Stojanovic ◽  
Zida Wu ◽  
Craig E Stiles ◽  
Dragana Miljic ◽  
Ivan Soldatovic ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Area Under The Curve ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Secretory Vesicles ◽  
Loss Of Function ◽  
Interacting Protein ◽  
Aryl Hydrocarbon ◽  
Immunometric Assay

Background Aryl hydrocarbon receptor-interacting protein (AIP) is evolutionarily conserved and expressed widely throughout the organism. Loss-of-function AIP mutations predispose to young-onset pituitary adenomas. AIP co-localizes with growth hormone in normal and tumorous somatotroph secretory vesicles. AIP protein is detectable in circulation. We aimed to investigate possible AIP and GH co-secretion, by studying serum AIP and GH levels at baseline and after GH stimulation or suppression, in GH deficiency (GHD) and in acromegaly patients. Subjects and methods Insulin tolerance test (ITT) was performed in GHD patients (n = 13) and age-BMI-matched normal GH axis control patients (n = 31). Oral glucose tolerance test (OGTT) was performed in active acromegaly patients (n = 26) and age-BMI-matched normal GH axis control patients (n = 18). In-house immunometric assay was developed for measuring circulating AIP. Results Serum AIP levels were in the 0.1 ng/mL range independently of gender, age or BMI. Baseline AIP did not differ between GHD and non-GHD or between acromegaly and patients with no acromegaly. There was no change in peak, trough or area under the curve during OGTT or ITT. Serum AIP did not correlate with GH during ITT or OGTT. Conclusions Human circulating serum AIP in vivo was assessed by a novel immunometric assay. AIP levels were independent of age, sex or BMI and unaffected by hypoglycaemia or hyperglycaemia. Despite co-localization in secretory vesicles, AIP and GH did not correlate at baseline or during GH stimulation or suppression tests. A platform of reliable serum AIP measurement is established for further research of its circulatory source, role and impact.

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