Habitual coffee consumption and risk of dementia in older persons: modulation by CYP1A2 polymorphism.

Higher coffee consumption has been associated with reduced dementia risk, yet with inconsistencies across studies. CYP1A2 polymorphisms, which affects caffeine metabolism, may modulate the association between coffee and the risk of dementia and Alzheimer's disease (AD). We included 5964 participants of the Three-City Study (mean age 74 years-old), free of dementia at baseline when they reported their daily coffee consumption, with available genome-wide genotyping and followed for dementia over a median of 9.0 (range 0.8-18.7) years. In Cox proportional-hazards models, the relationship between coffee consumption and dementia risk was modified by CYP1A2 polymorphism at rs762551 (p for interaction = 0.034). In multivariable-adjusted models, coffee intake was linearly associated with a decreased risk of dementia among carriers of the C allele only ("slower caffeine metabolizers"; HR for 1-cup increased [95% CI] 0.90 [0.83-0.97]), while in non-carriers ("faster caffeine metabolizers"), there was no significant association but a J-shaped trend toward a decrease in dementia risk up to 3 cups/day and increased risk beyond. Thus, compared to null intake, drinking ≥ 4 cups of coffee daily was associated with a reduced dementia risk in slower but not faster metabolizers (HR [95% CI] for ≥ 4 vs. 0 cup/day = 0.45 [0.25-0.80] and 1.32 [0.89-1.96], respectively). Results were similar when studying AD and another CYP1A2 candidate polymorphism (rs2472304), but no interaction was found with CYP1A2 rs2472297 or rs2470893. In this cohort, a linear association of coffee intake to lower dementia risk was apparent only among carriers of CYP1A2 polymorphisms predisposing to slower caffeine metabolism.

Caffeine, CYP1A2 Genotype, and Exercise Performance: A Systematic Review and Meta-analysis.

PURPOSE: This study aimed to summarize and meta-analyze existing evidence regarding the influence of CYP1A2 genotypes on the acute effects of caffeine for exercise performance and to investigate the interaction between genotype, dosage, and timing of caffeine supplementation. METHODS: Six databases were searched for studies determining the effect of caffeine (except mouth rinsing) on exercise performance between CYP1A2 genotypes. Three-level meta-analyses were performed using standardized mean differences (SMD; Hedge's g ) to determine the effect of caffeine on exercise outcomes within and between CYP1A2 genotypes (AA, AC, and CC). Meta-regressions were performed for dose, timing, and presence of reported conflict of interests (RCOI). A meta-analysis was also performed with placebo values to assess for imbalances between genotypes. RESULTS: Thirteen studies, totaling 119 outcomes and 440 participants, were included (233 AA, 175 AC, ad 34 CC). Caffeine improved performance for AA (SMD = 0.30, 95% confidence interval [CI] = 0.21-0.39, P < 0.0001) and AC (SMD = 0.16, 95% CI = 0.06-0.25, P = 0.022) but worsened performance for CC (SMD = -0.22, 95% CI = -0.44 to -0.01, P < 0.0001). Dose affected only CC, with greater doses generating more positive SMD (CC-dose estimate: +0.19/1 mg·kg -1 body mass, 95% CI = 0.04-0.33, P = 0.01). Timing influenced only CC, with better performance with later onset of exercise after supplementation (CC-timing estimate: +0.01/min, 95% CI = 0.00-0.02, P = 0.02). RCOI only affected SMD of CC (CC-RCOI estimate: -0.57, 95% CI = -1.02 to -0.12, P = 0.01). After excluding studies with RCOI, no influence of genotype was seen (all P ≥ 0.19). Small, nonsignificant differences were seen in placebo between genotypes (SMD AA vs CC: -0.13; AA vs AC: -0.12; AC vs CC: -0.05; all P ≥ 0.26). CONCLUSIONS: Caffeine improved performance for AA and AC but worsened performance for CC. Dose and timing moderated the efficacy of caffeine for CC only. Caution is advised because baseline differences and studies with RCOI could have influenced these results.

Prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) augments neonatal hyperoxic lung injury: Role of cytochrome P450 (CYP)1A1, 1A2, and 1B1.

Pregnant women exposed to polycyclic aromatic hydrocarbons (PAHs) are at increased risk for premature delivery. Premature infants often require supplemental oxygen, a known risk factor for bronchopulmonary dysplasia (BPD). Cytochrome P450 (CYP) enzymes have been implicated in hyperoxic lung injury. We hypothesize that prenatal PAH exposure exacerbates oxygen-mediated lung injury in neonatal mice, and that this effect is differentially altered in mice lacking the gene for (Cyp)1a1, 1a2, or 1b1. Timed pregnant wild type (WT) (C57BL/6J) mice were orally administered a PAH mixture of benzo[a]pyrene (BP) and benzo[b]fluoranthene (BbF) or the vehicle corn oil (CO) once daily on gestational days 16-19, and the dose response on postnatal lung injury was examined. In addition, timed pregnant mice with one of four genotypes, WT, Cyp1a1-null, Cyp1a2-null, and Cyp1b1-null, were treated orally with CO or PAH on gestational days 16-19 and exposed to hyperoxia or room air for 14 days. Lung injury was assessed on PND15 by radial alveolar count (RAC) and mean linear intercept (MLI) Gene expression of DNA repair genes in lung and liver were measured. Results showed that neonatal hyperoxic lung injury is augmented by prenatal PAH exposure in a dose-dependent manner. This effect was differentially altered in the Cyp-null mice, with Cyp1a2-null showing the greatest extent of lung injury. We concluded that newborn mice exposed to PAH in utero had more significant lung injury in response to hyperoxia than non-PAH exposed pups, and that CYP1A1 and CYP1A2 are protective against lung injury while CYP1B1 augments lung injury.

Utilizing plasma drug levels and genetic testing to achieve optimal treatment response in a patient with treatment-resistant schizoaffective disorder.

We report the case of a Chinese male with schizoaffective disorder, an active smoker and a nonresponder to clozapine (600 mg daily). Therapeutic clozapine monitoring was analyzed, revealing a low concentration-dose ratio. A pharmacogenetic test showed that the patient had the CYP1A2*1F/*1F genotype, indicating an ultra-rapid clozapine metabolizer. In combination with fluvoxamine, a CYP1A2 enzyme inhibitor, clozapine plasma concentrations approached the reference range and achieved clinical improvement. This case demonstrates how pharmacogenetics can help understand the value of therapeutic drug monitoring to enhance the treatment of refractory schizoaffective disorder.

[Modulation of Expression of Drug Metabolizing Enzymes and Augmentation of Anti-cancer Drug Effects: Through Epigenetics and Three-dimensional Cancer Cell Culture Systems].

Since commencing my role as a professor in a newly established Department of Pharmacodynamics and Molecular Genetics at the School of Pharmacy, Iwate Medical University, on April 1, 2007, my research has focused on modifying gene expression of cytochrome P-450 (CYP) in established human colon cancer cells. Additionally, I have been investigating methods to enhance the anti-tumor effects of irinotecan (CPT-11) and 5-fluorouracil (5-FU) using epigenetic modifying inhibitors of DNA methyltransferase and histone deacetylase. Treating colon cancer cells with a DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (DAC), led to elevated expression levels of CYP1B1 and CYP3A4 through demethylation of the promoter regions of related genes. Furthermore, the administration of DAC and the histone deacetylase inhibitor depsipeptide [(DEP), an anti-cancer drug romidepsin] significantly increased the cellular sensitivities of human colon cancer cells to CPT-11 and 5-FU, respectively. Remarkably, DAC treatment also increased colon cancer cell sensitivity to SN-38, an active metabolite of CPT-11, through the suppression of the anti-apoptotic protein Bcl-2. DEP increased colon cancer cell sensitivity to 5-FU in association with increased expressions of tumor-suppressor p21 and major histocompatibility complex class II genes. Another facet of my research is centered around understanding the gene regulatory mechanisms of the CYP1 family through aryl hydrocarbon receptors (AhR)s under glucose-deprivation stress and in three-dimensional (3D) culture systems of human solid tumor cells. In the 3D culture of human liver cancer cells, I found Pregnane X Receptor being implicated in the regulation of CYP1A2, which aligns with the in vivo mode of CYP1A2 expression.

Nutrigenomics: SNPs correlated to detoxification, antioxidant capacity and longevity.

Abstract: Nutritional genomics, also known as nutrigenomics, is the study of how a person's diet and genes interact with each other. The field of nutrigenomics aims to explain how common nutrients, food additives and preservatives can change the body's genetic balance towards either health or sickness. This study reviews the effects of SNPs on detoxification, antioxidant capacity, and longevity. SNPs are mutations that only change one nucleotide at a specific site in the DNA. Specific SNPs have been associated to a variety of biological processes, including detoxification, antioxidant capacity, and longevity. This article mainly focuses on the following genes: SOD2, AS3MT, CYP1A2, and ADO-RA2A (detoxification); LEPR, TCF7L2, KCNJ11, AMY1, and UCP3 (antioxidant capacity); FOXO3 and BPIFB4 (longevity). This review underlines that many genes-among which FOXO3, TCF7L2, LEPR, CYP1A2, ADORA2A, and SOD2-have a unique effect on a person's health, susceptibility to disease, and general well-being. Due to their important roles in numerous biological processes and their implications for health, these genes have undergone intensive research. Examining the SNPs in these genes can provide insight into how genetic variants affect individuals' responses to their environment, their likelihood of developing certain diseases, and their general state of health.

Evaluation of Supervised Machine Learning Algorithms and Computational Structural Validation of Single Nucleotide Polymorphisms Related to Acute Liver Injury with Paracetamol.

AIMS: To identify single nucleotide polymorphisms (SNPs) of paracetamol-metabolizing enzymes that can predict acute liver injury. BACKGROUND: Paracetamol is a commonly administered analgesic/antipyretic in critically ill and chronic renal failure patients and several SNPs influence the therapeutic and toxic effects. OBJECTIVE: To evaluate the role of machine learning algorithms (MLAs) and bioinformatics tools to delineate the predictor SNPs as well as to understand their molecular dynamics. METHODS: A cross-sectional study was undertaken by recruiting critically ill patients with chronic renal failure and administering intravenous paracetamol as a standard of care. Serum concentrations of paracetamol and the principal metabolites were estimated. Following SNPs were evaluated: CYP2E1*2, CYP2E1_-1295G>C, CYP2D6*10, CYP3A4*1B, CYP3A4*2, CYP1A2*1K, CYP1A2*6, CYP3A4*3, and CYP3A5*7. MLAs were used to identify the predictor genetic variable for acute liver failure. Bioinformatics tools such as Predict SNP2 and molecular docking (MD) were undertaken to evaluate the impact of the above SNPs with binding affinity to paracetamol. RESULTS: CYP2E1*2 and CYP1A2*1C genotypes were identified by MLAs to significantly predict hepatotoxicity. The predictSNP2 revealed that CYP1A2*3 was highly deleterious in all the tools. MD revealed binding energy of -5.5 Kcal/mol, -6.9 Kcal/mol, and -6.8 Kcal/mol for CYP1A2, CYP1A2*3, and CYP1A2*6 against paracetamol. MD simulations revealed that CYP1A2*3 and CYP1A2*6 missense variants in CYP1A2 affect the binding ability with paracetamol. In-silico techniques found that CYP1A2*2 and CYP1A2*6 are highly harmful. MD simulations revealed CYP3A4*2 (A>G) had decreased binding energy with paracetamol than CYP3A4, and CYP3A4*2(A>T) and CYP3A4*3 both have greater binding energy with paracetamol. CONCLUSION: Polymorphisms in CYP2E1, CYP1A2, CYP3A4, and CYP3A5 significantly influence paracetamol's clinical outcomes or binding affinity. Robust clinical studies are needed to identify these polymorphisms' clinical impact on the pharmacokinetics or pharmacodynamics of paracetamol.

CYP1A2 expression rather than genotype is associated with olanzapine concentration in psychiatric patients.

Olanzapine is a commonly prescribed atypical antipsychotic agent for treatment of patients with schizophrenia and bipolar disorders. Previous in vitro studies using human liver microsomes identified CYP1A2 and CYP2D6 enzymes being responsible for CYP-mediated metabolism of olanzapine. The present work focused on the impact of CYP1A2 and CYP2D6 genetic polymorphisms as well as of CYP1A2 metabolizing capacity influenced by non-genetic factors (sex, age, smoking) on olanzapine blood concentration in patients with psychiatric disorders (N = 139). CYP2D6 genotype-based phenotype appeared to have negligible contribution to olanzapine metabolism, whereas a dominant role of CYP1A2 in olanzapine exposure was confirmed. However, CYP1A2 expression rather than CYP1A2 genetic variability was demonstrated to be associated with olanzapine concentration in patients. Significant contribution of - 163C > A (rs762551), the most common SNP (single nucleotide polymorphism) in CYP1A2 gene, to enhanced inducibility was confirmed by an increase in CYP1A2 mRNA expression in smokers carrying - 163A, and smoking was found to have appreciable impact on olanzapine concentration normalized by the dose/bodyweight. Furthermore, patients' olanzapine exposure was in strong association with CYP1A2 expression; therefore, assaying CYP1A2 mRNA level in leukocytes can be an appropriate tool for the estimation of patients' olanzapine metabolizing capacity and may be relevant in optimizing olanzapine dosage.

The Impact of the CYP2D6 and CYP1A2 Gene Polymorphisms on Response to Duloxetine in Patients with Major Depression.

Depression is a global mental health concern, and personalized treatment approaches are needed to optimize its management. This study aimed to investigate the influence of the CYP2D6 and CYP1A2 gene polymorphisms on the efficacy of duloxetine in reducing depressive and anxiety symptoms. A sample of 100 outpatients with major depression, who initiated monotherapy with duloxetine, were followed up. Polymorphisms in the CYP2D6 and CYP1A2 genes were assessed. The severity of depressive and anxiety symptoms was recorded using standardized scales. Adverse drug reactions (ADRs) were analyzed. Statistical analyses, including linear regression, were conducted to examine the relationships between genetic polymorphisms, clinical variables, and treatment outcomes. Patients with higher values of the duloxetine metabolic index (DMI) for CYP2D6, indicating a faster metabolism, achieved a greater reduction in anxiety symptoms. The occurrence of ADRs was associated with a lower reduction in anxiety symptoms. However, no significant associations were found between studied gene polymorphisms and reduction in depressive symptoms. No significant effects of the DMI for CYP1A2 were found. Patients with a slower metabolism may experience less benefit from duloxetine therapy in terms of anxiety symptom reduction. Personalizing treatment based on the CYP2D6 and CYP1A2 gene polymorphisms can enhance the effectiveness of antidepressant therapy and improve patient outcomes.

Single Mutations in Cytochrome P450 Oxidoreductase Can Alter the Specificity of Human Cytochrome P450 1A2-Mediated Caffeine Metabolism.

A unique cytochrome P450 (CYP) oxidoreductase (CPR) sustains activities of human microsomal CYPs. Its function requires toggling between a closed conformation enabling electron transfers from NADPH to FAD and then FMN cofactors and open conformations forming complexes and transferring electrons to CYPs. We previously demonstrated that distinct features of the hinge region linking the FAD and FMN domain (FD) modulate conformer poses and their interactions with CYPs. Specific FD residues contribute in a CYP isoform-dependent manner to the recognition and electron transfer mechanisms that are additionally modulated by the structure of CYP-bound substrate. To obtain insights into the underlying mechanisms, we analyzed how hinge region and FD mutations influence CYP1A2-mediated caffeine metabolism. Activities, metabolite profiles, regiospecificity and coupling efficiencies were evaluated in regard to the structural features and molecular dynamics of complexes bearing alternate substrate poses at the CYP active site. Studies reveal that FD variants not only modulate CYP activities but surprisingly the regiospecificity of reactions. Computational approaches evidenced that the considered mutations are generally in close contact with residues at the FD-CYP interface, exhibiting induced fits during complexation and modified dynamics depending on caffeine presence and orientation. It was concluded that dynamic coupling between FD mutations, the complex interface and CYP active site exist consistently with the observed regiospecific alterations.

Arsenic trioxide (ATO) up-regulates cytochrome P450 1A (CYP1A) enzymes in murine hepatoma Hepa-1c1c7 cell line.

Arsenic trioxide (ATO) is a highly toxic arsenical which has been successfully exploited for treating acute promyelocytic leukemia (APL). Unfortunately, its therapeutic efficacy is accompanied by serious toxicities with undeciphered mechanisms. Cytochrome P450 1A (CYP1A) enzymes undergo modulation by arsenicals, with ensuing critical consequences regarding drug clearance or procarcinogen activation. Here, we investigated the potential of ATO to alter basal and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced CYP1A1/1A2 expressions. Mouse-derived hepatoma Hepa-1c1c7 cells were exposed to 0.63, 1.25, and 2.5 µM ATO with or without 1 nM TCDD. ATO increased TCDD-induced CYP1A1/1A2 mRNA, protein, and activity. Constitutively, ATO induced Cyp1a1/1a2 transcripts and CYP1A2 protein. ATO increased AHR nuclear accumulation and subsequently increased XRE-luciferase reporter activity. ATO enhanced CYP1A1 mRNA and protein stabilities. In conclusion, ATO up-regulates CYP1A in Hepa-1c1c7 cells transcriptionally, post-transcriptionally, and post-translationally. Therefore, ATO can be implicated in clearance-related interactions with CYP1A1/1A2 substrates, or in excessive activation of environmental procarcinogens.

The Potential Role of POR*28 and CYP1A2*F Genetic Variations and Lifestyle Factors on Clozapine and N-DesmethylClozapine Plasma Levels in Schizophrenia Patients.

BACKGROUND: Despite its advantages over other antipsychotics, for treatment-resistant schizophrenia, clinical use of Clozapine (CLZ) is challenging by its narrow therapeutic index and potentially life-threatening dose-related adverse effects. RESEARCH DESIGN AND METHODS: As the potential role in CLZ metabolism is assigned to CYP1A2 enzyme and consequently Cytochrome P450 oxidoreductase (POR) their genetic variations might help to determine CLZ levels in schizophrenia patients. For this purpose, 112 schizophrenia patients receiving CLZ were included in the current study. Plasma CLZ and N-desmethylclozapine (DCLZ) levels were analyzed by using HPLC and genetic variations were identified with the PCR-RFLP method. RESULTS: The patients' CYP1A2 and POR genotypes seemed to not affect plasma CLZ and DCLZ levels whereas in the subgroup analysis, POR *28 genotype significantly influenced simple and adjusted plasma CLZ and DLCZ levels concerning smoking habit and caffeine consumption. CONCLUSIONS: The findings of the present study highlight the importance of both genetic and non-genetic factors (smoking and caffeine consumption) for the individualization of the CLZ treatment. In addition to that, it suggests that the added utility of not only the CLZ metabolizing enzymes but also POR, which is crucial for proper CYP activity, to guide CLZ dosing might be useful for clinical decision-making.

Loss of cytochrome P450 (CYP)1B1 mitigates hyperoxia response in adult mouse lung by reprogramming metabolism and translation.

Oxygen supplementation is life saving for premature infants and for COVID-19 patients but can induce long-term pulmonary injury by triggering inflammation, with xenobiotic-metabolizing CYP enzymes playing a critical role. Murine studies showed that CYP1B1 enhances, while CYP1A1 and CYP1A2 protect from, hyperoxic lung injury. In this study we tested the hypothesis that Cyp1b1-null mice would revert hyperoxia-induced transcriptomic changes observed in WT mice at the transcript and pathway level. Wild type (WT) C57BL/6J and Cyp1b1-null mice aged 8-10 weeks were maintained in room air (21% O2) or exposed to hyperoxia (>95% O2) for 48h. Transcriptomic profiling was conducted using the Illumina microarray platform. Hyperoxia exposure led to robust changes in gene expression and in the same direction in WT, Cyp1a1-, Cyp1a2-, and Cyp1b1-null mice, but to different extents for each mouse genotype. At the transcriptome level, all Cyp1-null murine models reversed hyperoxia effects. Gene Set Enrichment Analysis identified 118 hyperoxia-affected pathways mitigated only in Cyp1b1-null mice, including lipid, glutamate, and amino acid metabolism. Cell cycle genes Cdkn1a and Ccnd1 were induced by hyperoxia in both WT and Cyp1b1-null mice but mitigated in Cyp1b1-null O2 compared to WT O2 mice. Hyperoxia gene signatures associated positively with bronchopulmonary dysplasia (BPD), which occurs in premature infants (with supplemental oxygen being one of the risk factors), but only in the Cyp1b1-null mice did the gene profile after hyperoxia exposure show a partial rescue of BPD-associated transcriptome. Our study suggests that CYP1B1 plays a pro-oxidant role in hyperoxia-induced lung injury.

The alteration of drug metabolism enzymes and pharmacokinetic parameters in nonalcoholic fatty liver disease: current animal models and clinical practice.

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease. The whole concept of NAFLD has now moved into metabolic dysfunction-associated fatty liver disease (MAFLD) to emphasize the strong metabolic derangement as the basis of the disease. Several studies have suggested that hepatic gene expression was altered in NAFLD and NAFLD-related metabolic comorbidities, particularly mRNA and protein expression of phase I and II drug metabolism enzymes (DMEs). NAFLD may affect the pharmacokinetic parameters. However, there were a limited number of pharmacokinetic studies on NAFLD at present. Determining the pharmacokinetic variation in patients with NAFLD remains challenging. Common modalities for modeling NAFLD included: dietary induction, chemical induction, or genetic models. The altered expression of DMEs has been found in rodent and human samples with NAFLD and NAFLD-related metabolic comorbidities. We summarized the pharmacokinetic changes of clozapine (CYP1A2 substrate), caffeine (CYP1A2 substrate), omeprazole (Cyp2c29/CYP2C19 substrate), chlorzoxazone (CYP2E1 substrate), midazolam (Cyp3a11/CYP3A4 substrate) in NAFLD. These results led us to wonder whether current drug dosage recommendations may need to be reevaluated. More objective and rigorous studies are required to confirm these pharmacokinetic changes. We have also summarized the substrates of the DMEs aforementioned. In conclusion, DMEs play an important role in the metabolism of drugs. We hope that future investigations should focus on the effect and alteration of DMEs and pharmacokinetic parameters in this special patient population with NAFLD.

Genetics of caffeine and brain-related outcomes - a systematic review of observational studies and randomized trials.

CONTEXT: Although the stimulant and anxiogenic properties of caffeine are widely accepted, research on its specific effects on the brain remains controversial. Growing evidence shows that interindividual differences in caffeine response may be partly due to variations in genes such as CYP1A2 and ADORA2A, which have been used to identify individuals as "fast" or "slow" caffeine metabolizers and as having a "high" or "low" caffeine sensitivity, respectively. OBJECTIVE: The objective of this review was to identify, evaluate, and discuss current evidence on the associations between common genetic variants, caffeine consumption, and brain-related outcomes in humans. DATA SOURCES: PubMed and Embase databases were searched for relevant reports based on a predetermined search strategy. DATA EXTRACTION: Reports of observational and experimental studies on healthy adults who underwent (a) genetic analysis for polymorphisms in genes associated with caffeine metabolism and effects and (b) measurements of brain-related effects such as anxiety, insomnia, and cognitive performance associated with the consumption of caffeine (habitual intake or supplementation) were included. DATA ANALYSIS: Of the 22 records included, 15 were randomized controlled trials, 6 were cross-sectional studies, and 1 was a genome-wide association study. The main outcomes identified were cognitive performance (n = 9), anxiety (n = 7), and sleep disturbance/insomnia (n = 6). Polymorphisms in the CYP1A2 gene were associated with cognitive function, while variations in the ADORA2A gene were associated with anxiety and sleep disturbance. CONCLUSION: The present review has provided evidence that variability in the CYP1A2 and the ADORA2A genes may modulate the association between caffeine and brain-related outcomes. Future studies are warranted to investigate the specific polymorphisms implicated in each brain outcome, which cognitive functions are particularly related to caffeine (simple vs complex), whether there are gender differences in anxiety effects, and how habitual caffeine intake may influence the acute effects of caffeine. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42021257556.

The ADORA2A TT Genotype Is Associated with Anti-Inflammatory Effects of Caffeine in Response to Resistance Exercise and Habitual Coffee Intake.

Caffeine is an adenosine A2A receptor (ADORA2A) antagonist with ergogenic and anti-inflammatory effects. Previous studies have reported that the ADORA2A gene regulates glutamate metabolism and immune responses, with the ADORA2A rs5751876 TT genotype (with high sensitivity to caffeine) showing larger ergogenic effect following caffeine ingestion. We therefore hypothesized that the TT genotype would be associated with greater anti-inflammatory effects of caffeine in response to exercise, and with higher coffee intake in physically active individuals. The aim of the present study was twofold: (1) to investigate the association of the ADORA2A variant with the anti-inflammatory effects of caffeine in response to intense resistance exercise (RE), and (2) to analyze the association of the rs5751876 with coffee intake in physically active individuals (n = 134). Fifteen resistance-trained athletes participated in a randomized, double-blind, placebo-controlled cross-over study, where they consumed 6 mg/kg of caffeine or placebo one hour prior to performing an RE protocol. Blood samples were taken immediately from the arterial vein before, immediately after, and 15 min after RE for the analysis of inflammatory markers myeloperoxidase (MPO) and acetylcholinesterase (AChE). We found that the ADORA2A TT genotype carriers experienced lower exercise-induced inflammatory responses (p < 0.05 for AchE) when compared to the C allele carriers (i.e., CC/CT) one hour following the ingestion of caffeine. Furthermore, the ADORA2A TT genotype was positively associated with coffee intake (p = 0.0143; irrespective of CYP1A2 rs762551 polymorphism). In conclusion, we found that the ADORA2A gene polymorphism is associated with anti-inflammatory effects of caffeine in response to resistance exercise, as well as with habitual coffee intake in physically active individuals.

Effects of xenobiotics on CYP1 enzyme-mediated biotransformation and bioactivation of estradiol.

Endogenous estradiol (E2) exerts diverse physiological and pharmacological activities, commonly used for hormone replacement therapy. However, prolonged and excessive exposure to E2 potentially increases estrogenic cancer risk. Reportedly, CYP1 enzyme-mediated biotransformation of E2 is largely concerned with its balance between detoxification and carcinogenic pathways. Among the three key CYP1 enzymes (CYP1A1, CYP1A2, and CYP1B1), CYP1A1 and CYP1A2 mainly catalyze the formation of nontoxic 2-hydroxyestradiol (2-OH-E2), while CYP1B1 specifically catalyzes the formation of genotoxic 4-hydroxyestradiol (4-OH-E2). 4-OH-E2 can be further metabolized to electrophilic quinone intermediates accompanied by the generation of reactive oxygen species (ROS), triggering DNA damage. Since abnormal alterations in CYP1 activities can greatly affect the bioactivation process of E2, regulatory effects of xenobiotics on CYP1s are essential for E2-associated cancer development. To date, thousands of natural and synthetic compounds have been found to show potential inhibition and/or induction actions on the three CYP1 members. Generally, these chemicals share similar planar polycyclic skeletons, the structural motifs and substituent groups of which are important for their inhibitory/inductive efficiency and selectivity toward CYP1 enzymes. This review comprehensively summarizes these known inhibitors and/or inductors of E2-metabolizing CYP1s based on chemical categories and discusses their structure-activity relationships, which would contribute to better understanding of the correlation between xenobiotic-regulated CYP1 activities and estrogenic cancer susceptibility.

The impact of genetic variability on the relationship between caffeine and cardiometabolic outcomes: A systematic review.

The relationship between caffeine consumption and cardiometabolic health has been reported, however with heterogenous results. Discrepancies in study results may be due to inter-individual variability between study participants. This systematic review aimed to identify the impact of genetics on the relationship between caffeine consumption and cardiometabolic outcomes. Electronic databases (PubMed and EMBASE) were searched for studies published until July 2021. Selected studies were of both intervention and observational design and included (1) analysis of at least one of the selected cardiometabolic outcome (type 2 diabetes, glucose/insulin levels, cardiovascular disease [CVD], blood pressure [BP] or hypertension, and blood lipid and catecholamine levels), (2) adults aged 18-65 years, and (3) genetic analysis of individuals consuming caffeine. Seventeen studies were included: four randomised controlled trials and an interventional and quasi-experimental study, six population-based prospective cohort studies, three cross-sectional studies, and three case-control studies. CYP1A2 rs762551 and ADORA rs5751876 were associated with glucose response when caffeine was consumed with carbohydrates. CYP1A2 rs762551 moderated the association between coffee intake and hypertension. Moreover, ADORA2A rs5751876 and the ADRA2B I variants moderated the associations between caffeine and BP. Studies that investigated the effects of genetic variations on CVD and caffeine consumption reported equivocal findings (CYP1A2) or warrant replication (COMT, ADORA and TRIB1). Elucidating the extent to which these genes moderate the association between caffeine and cardiometabolic outcomes will enable caffeine consumption advice to be tailored to specific individuals to optimise health.

Genic-intergenic polymorphisms of CYP1A genes and their clinical impact.

The humancytochrome P450 1A (CYP1A) subfamily genes, CYP1A1 and CYP1A2, encoding monooxygenases are critically involved in biotransformation of key endogenous substrates (estradiol, arachidonic acid, cholesterol) and exogenous compounds (smoke constituents, carcinogens, caffeine, therapeutic drugs). This suggests their significant involvement in multiple biological pathways with a primary role of maintaining endogenous homeostasis and xenobiotic detoxification. Large interindividual variability exist in CYP1A gene expression and/or catalytic activity of the enzyme, which is primarily due to the existence of polymorphic alleles which encode them. These polymorphisms (mainly single nucleotide polymorphisms, SNPs) have been extensively studied as susceptibility factors in a spectrum of clinical phenotypes. An in-depth understanding of the effects of polymorphic CYP1A genes on the differential metabolic activity and the resulting biological pathways is needed to explain the clinical implications of CYP1A polymorphisms. The present review is intended to provide an integrated understanding of CYP1A metabolic activity with unique substrate specificity and their involvement in physiological and pathophysiological roles. The article further emphasizes on the impact of widely studied CYP1A1 and CYP1A2 SNPs and their complex interaction with non-genetic factors like smoking and caffeine intake on multiple clinical phenotypes. Finally, we attempted to discuss the alterations in metabolism/physiology concerning the polymorphic CYP1A genes, which may underlie the reported clinical associations. This knowledge may provide insights into the disease pathogenesis, risk stratification, response to therapy and potential drug targets for individuals with certain CYP1A genotypes.