Role Of CYP1A1 Research Articles

What is the role of CYP1A1 in drug metabolism?

What is the role of CYP1A1 in drug metabolism?

Genome-wide Association Study of Caffeine Consumption Using Coriell Personalized Medicine Collaborative Data

More than 90% of Americans consume caffeine daily, but the amount consumed varies widely. Previous studies have shown that genes related to caffeine metabolism and receptor binding may influence caffeine consumption. A better understanding of the relationship between genotype and caffeine consumption has the potential to inform mechanisms of this common dietary behavior. We performed a genome-wide association study (GWAS) of self-reported consumption data combining a wide range of caffeinated beverages including coffee, tea, soda, and energy drinks in the Coriell Personalized Medicine Collaborative (N=2,830) using a generalized linear model. Our analysis identified several candidate loci implicated in caffeine consumption. One previously identified SNP associated with caffeine consumption and replicated in the current study, rs2472297 (P-value=3.8x10-6), is located in an intergenic region between CYP1A1 and CYP1A2 (the gene that encodes the enzyme primarily responsible for caffeine metabolism), and has been associated with caffeine consumption in prior studies. Our results further support follow-up functional studies focused on the role of CYP1A1 and CYP1A2 on caffeine consumption habits, metabolism, and health status and outcomes.

A computational study on the biotransformation of alkenylbenzenes by a selection of CYPs: Reflections on their possible bioactivation

Alkenylbenzenes are aromatic compounds found in several vegetable foods that can cause genotoxicity upon bioactivation by members of the cytochrome P450 (CYP) family, forming 1′-hydroxy metabolites. These intermediates act as proximate carcinogens and can be further converted into reactive 1′-sulfooxy metabolites, which are the ultimate carcinogens responsible for genotoxicity. Safrole, a member of this class, has been banned as a food or feed additive in many countries based on its genotoxicity and carcinogenicity. However, it can still enter the food and feed chain. There is limited information about the toxicity of other alkenylbenzenes that may be present in safrole-containing foods, such as myristicin, apiole, and dillapiole. In vitro studies showed safrole as mainly bioactivated by CYP2A6 to form its proximate carcinogen, while for myristicin this is mainly done by CYP1A1. However, it is not known whether CYP1A1 and CYP2A6 can activate apiole and dillapiole. The present study uses an in silico pipeline to investigate this knowledge gap and determine whether CYP1A1 and CYP2A6 may play a role in the bioactivation of these alkenylbenzenes. The study found that the bioactivation of apiole and dillapiole by CYP1A1 and CYP2A6 is limited, possibly indicating that these compounds may have limited toxicity, while describing a possible role of CYP1A1 in the bioactivation of safrole. The study expands the current understanding of safrole toxicity and bioactivation and helps understand the mechanisms of CYPs involved in the bioactivation of alkenylbenzenes. This information is essential for a more informed analysis of alkenylbenzenes toxicity and risk assessment.

Role of CYP1A1, CYP2D6, and NOS3 gene polymorphisms in idiopathic recurrent pregnancy loss in the Iranian Azeri population: A case-control study.

Background It is estimated that 1-5% of couples suffer from recurrent pregnancy loss (RPL). Recent studies have shown the effects of gene polymorphisms in RPL.ObjectiveThe aim of this study was to evaluate 3 gene polymorphisms including rs1048943 of CYP1A1, rs28371725 of CYP2D6, and rs7830 of NOS3 in idiopathic RPL to identify their association with RPL.Materials and MethodsBlood samples were collected from 136 women with at least 2 consecutive idiopathic miscarriages (case group) and 136 women with no history of miscarriage and at least one successful pregnancy (control group) from the Iranian Azeri population. This study was carried out between April 2018-April 2020. Amplification-refractory mutation system polymerase chain reaction was used for the rs7830, rs1048943 and rs28371725 polymorphisms in order to genotype each extracted genomic DNA sample. After that, Chi-square, Fisher's exact test and logistic regression were used to investigate whether each of these polymorphisms is associated with RPL.ResultsAmong these polymorphisms, only rs1048943 of CYP1A1 showed a statistically significant association with RPL in the Iranian Azeri women studied.ConclusionOur results suggest that CYP1A1 gene polymorphisms might be associated with a reduced risk of RPL. Further studies in other populations and in the same population with a larger sample size, as well as functional genomics analyses such as gene expression analyses or epigenetic studies are required to validate our results.

Role of CYP2A6 in Methimazole Bioactivation and Hepatotoxicity.

Methimazole (MMI) is a widely used antithyroid drug, but it can cause hepatotoxicity by unknown mechanisms. Previous studies showed that the hepatic metabolism of MMI produces N-methylthiourea, leading to liver damage. However, the specific enzyme responsible for the production of the toxic metabolite N-methylthiourea is still unclear. In this study, we screened cytochromes P450 (CYPs) in N-methylthiourea production from MMI. CYP2A6 was identified as the key enzyme in catalyzing MMI metabolism to produce N-methylthiourea. When mice were pretreated with a CYP2A6 inhibitor, formation of N-methylthiourea from MMI was remarkably reduced. Consistently, the CYP2A6 inhibitor prevented MMI-induced hepatotoxicity. These results demonstrated that CYP2A6 is essential in MMI bioactivation and hepatotoxicity.

The role of CYP 1A1 and ERNX1 gene polymorphisms in oxidative stress mechanisms in patients with vibration disease

A correlation was detected between genotype (A/G), Cyp1A1*2C and maintenance of KB y=0,49, р=0,0013 and the ratio of SH/SS у=-0,44, р=0,0023 also found correlation between genotype (A/G) gene EPXH1 A-415G and the ratio of SH/ SS у=-0,46, р=0,0023 and content of SS-groups у=0,41, р=0,0068 in the patients examined.

Role of CYP1A1, ABCG2, CYP24A1 and VDR gene polymorphisms on the evaluation of cardiac iron overload in thalassaemia patients.

Iron-burden-induced arrhythmia and heart failure are among the leading causes of morbidity and mortality in β-thalassaemia major patients. T2* cardiac magnetic resonance remains the only reliable noninvasive method for the heart iron excess assessment. We explored the role of single nucleotide polymorphisms involved in vitamin D metabolism, transport and activity and in deferasirox (DFX) metabolism on cardiac iron burden. One hundred and five β-thalassaemia patients, treated with DFX, were enrolled in the present study. Drug plasma Ctrough was measured by a high-performance liquid chromatography-ultraviolet method. Allelic discrimination was carried out using the real-time PCR. CYP1A1*1189 CC, ABCG2 421 GA, CYP24A1 8620 GG and VDR TaqI CC single nucleotide polymorphisms influenced T2* values. Age, serum ferritin, ABCG2 421 GA, ABCG2 1194 +928 TC/CC, CYP24A1 22776 TT and VDR TaqI TC/CC were retained in linear regression model. Our results suggested, for the first time, the role of DFX and vitamin D pharmacogenetics on cardiac iron overload.

Abstract P3-12-07: Pharmacogenetic determinants of aromatase inhibitors pharmacokinetics and side effects: 6-month results of the adjuvant breast cancer longitudinal PHACS study (NCT01127295)

Abstract Supported by a PHRC grant (#09-18-005) Background: Recent literature has suggested that germline genetic variants of drug-metabolizing enzymes or CYP19A1 (coding for aromatase) may be involved in the systemic aromatase inhibitors (AI) concentrations or the occurrence of side effects (Hertz et al. Pharmacogenomics 2017). A prospective multicentre 3-year follow-up study was carried out to investigate the relationships between pharmacogenetics (PG), pharmacokinetics (PK) and toxicity in breast cancer patients treated with adjuvant AI (n=1098) or tamoxifen (n=879). The clinical results and the tamoxifen PG/PK analyses are described elsewhere (abstracts #851544 and #850248). Methods: SNP genotyping of 95 SNPs was performed on the Biomark (Fluidigm) with Taqman assays and was available for 373, 515 and 151 patients treated with anastrozole (ANA), letrozole (LETRO) and exemestane (EXE) respectively. CYP2A6 metaboliser status (MS) (poor, intermediate or normal) was determined based on alleles function (*1, *9, *2) and number of CYP2A6 copies. Trough plasma concentrations of each drug were determined 6 months after the start of the study by UPLC-MS/MS and were available for 342, 463 and 130 patients of the ANA, LETRO and EXE arms. Patients with AI concentrations below the limit of quantification were excluded for non-compliance (9 patients for ANA, 8 patients for LETRO and 7 patients for EXE). Toxicity was measured as a binary outcome (occurrence or worsening of hot flushes, fatigue, pain, arthralgia, vaginal dryness). All genetic associations were adjusted for multiple testing. Results: ANA concentration was significantly higher in patients experiencing pain (p=0.025) and was associated with rs28365063 (UGT2B7 g.372A>G). LETRO concentrations were strongly associated with CYP2A6 metabolizer status (p=0.0001) but did not differ in patients with or without toxicity. In the EXE arm, patients with hot flushes or arthralgia had a significantly lower level of exemestane (p= 0.0002 and p=0.023 respectively) but since the metabolism of EXE leads to active 17-hydroexemestane, we can hypothesize that the lower EXE concentration is an indirect reflection of the metabolite formation. A SNP (rs2307424) in NR1I3 gene (coding for the constitutive androstane receptor CAR) was associated with EXE concentrations. CAR has been shown to regulate CYP2B6, which is involved in the formation of 6-hydroxy-methyl-exemestane (inactive metabolite). Regarding the relationships between PG and toxicity, in the ANA arm, 3 SNPs of CYP19A1 gene tended to be associated with hot flushes worsening (rs934635) and arthralgia (rs10046 and rs2304463) but did not remain significant after multiple tests correction. In the EXE arm, several SNPs in NR1I3 gene were associated with fatigue. In the LETRO arm, patients with a poor CYP2A6 MS had a higher risk of experiencing depression. Conclusions: Our study confirms the predominant role of CYP2A6 in LETRO PK. To our knowledge, this is the first study to report on the role of UGT2B7 rs28365063 in ANA and NR1I3 in EXE PK and side effects. These relationships need to be re-evaluated with the drug concentrations obtained during the 3-year follow-up. Citation Format: Thomas F, Marquet P, Pinguet F, White-Koning M, Robert J, Tafzi N, Solassol I, Despax R, Levasseur N, Ellis S, Massoubre A, Mbatchi L, Le Morvan V, Roché H, Chatelut E, Evrard A. Pharmacogenetic determinants of aromatase inhibitors pharmacokinetics and side effects: 6-month results of the adjuvant breast cancer longitudinal PHACS study (NCT01127295) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-12-07.

Induction of CYP1A1 increases gefitinib-induced oxidative stress and apoptosis in A549 cells

As the first selective EGFR tyrosine kinase inhibitor, gefitinib has been clinically demonstrated to be effective for certain cancer cell types with EGFR-active gene mutations. However, a number of gefitinib-associated adverse pulmonary events have been reported, which could lead to the discontinuation of gefitinib therapy. Although previous reports have implicated that CYP1A1-mediated bioactivation of gefitinib maybe a major reason for the pulmonary toxicity, the roles of CYP1A1 in gefitinib-associated toxicity and the related molecular mechanism have not been well-characterized. This study aimed to reveal whether the induction of CYP1A1 would contribute to the toxic effect of gefitinib in living cells and to investigate the underlying molecular mechanism. The results demonstrated that gefitinib led to the enhancement of the dose-dependent cytotoxicity and the percentage of gefitinib-induced apoptosis was significantly increased on CYP1A1-overexpressed A549 cells, which was accompanied with a substantial increase in the intracellular reactive oxygen species and a remarkable decrease in the mitochondrial membrane potential. These findings strongly suggest that CYP1A1 can enhance the cytotoxicity of gefitinib and gefitinib-induced oxidative stress, which may partially explain the occurrence of pulmonary toxicity in some patients administered with gefitinib.

Role of CYP1A1 in the biological activity of methylated resveratrol analogue, 3,4,5,4′-tetramethoxystilbene (DMU-212) in ovarian cancer A-2780 and non-cancerous HOSE cells

The role of CYP1A1 and CYP1B1 enzymes in the biotransformation and biological activity of the methylated resveratrol analogue, 3,4,5,4′-tetramethoxystilbene (DMU-212) is still elusive. Our recently published data have shown that one of the metabolites of DMU-212, 3′-hydroxy-3,4,5,4′-tetramethoxystilbene (DMU-214) exerts more potent cytotoxic effects in A-2780 ovarian cancer cell line, as compared to the parent compound. Hence, this study aims to elucidate whether the biological activity of DMU-212 is related to its biotransformation to DMU-214. Furthermore, we aimed to assess which enzymes of CYP1 family are involved in the biotransformation of DMU-212. The human ovarian cancer cell lines A-2780, A-2780CYP1A1(−) and non-cancerous human ovarian surface epithelial (HOSE) cells were employed in the present study.In contrary to other authors’ suggestions we have found that CYP1A1 is the major enzyme of CYP1 family involved in the metabolic activation of DMU-212. Since the distinctly weaker anti-proliferative effects of DMU-212 against HOSE and A-2780CYP1A1(−) cells have been associated with the lack of the expression of CYP1A1, we suggest that the biological activity of the parent compound may be related to its metabolic activation to DMU-214 and the level of this enzyme.

Role of CYP1A1 in modulating the vascular and blood pressure benefits of omega-3 polyunsaturated fatty acids.

The mechanisms that mediate the cardiovascular protective effects of omega 3 (n-3) polyunsaturated fatty acids (PUFAs) have not been fully elucidated. Cytochrome P450 1A1 efficiently metabolizes n-3 PUFAs to potent vasodilators. Thus, we hypothesized that dietary n-3 PUFAs increase nitric oxide (NO)-dependent blood pressure regulation and vasodilation in a CYP1A1-dependent manner. CYP1A1 wild-type (WT) and knockout (KO) mice were fed an n-3 or n-6 PUFA-enriched diet for 8 weeks and were analyzed for tissue fatty acids and metabolites, NO-dependent blood pressure regulation, NO-dependent vasodilation of acetylcholine (ACh) in mesenteric resistance arterioles, and endothelial NO synthase (eNOS) and phospho-Ser1177-eNOS expression in the aorta. All mice fed the n-3 PUFA diet showed significantly higher levels of n-3 PUFAs and their metabolites, and significantly lower levels of n-6 PUFAs and their metabolites. In addition, KO mice on the n-3 PUFA diet accumulated significantly higher levels of n-3 PUFAs in the aorta and kidney without a parallel increase in the levels of their metabolites. Moreover, KO mice exhibited significantly less NO-dependent regulation of blood pressure on the n-3 PUFA diet and significantly less NO-dependent, ACh-mediated vasodilation in mesenteric arterioles on both diets. Finally, the n-3 PUFA diet significantly increased aortic phospho-Ser1177-eNOS/eNOS ratio in the WT compared with KO mice. These data demonstrate that CYP1A1 contributes to eNOS activation, NO bioavailability, and NO-dependent blood pressure regulation mediated by dietary n-3 PUFAs.

The cytochrome P450-catalyzed metabolism of levomepromazine: a phenothiazine neuroleptic with a wide spectrum of clinical application

The aim of the present study was to identify cytochrome P450 isoenzymes (CYPs) involved in the 5-sulfoxidation and N-demethylation of the aliphatic-type phenothiazine neuroleptic levomepromazine in human liver. Experiments were performed in vitro using cDNA-expressed human CYP isoforms (Supersomes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4), liver microsomes from different donors and CYP-selective inhibitors. The obtained results indicate that CYP3A4 is the main isoform responsible for levomepromazine 5-sulfoxidation (72%) and N-demethylation (78%) at a therapeutic concentration of the drug (10μM). CYP1A2 contributes to a lesser degree to levomepromazine 5-sulfoxidation (20%). The role of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 in catalyzing the above-mentioned reactions is negligible (0.1–8%). Moreover, at a higher, toxicological concentration of the neuroleptic (100μM), the relative contribution of CYP1A2 to levomepromazine metabolism visibly increases (from 20% to 28% for 5-sufoxidation, and from 8% to 32% for N-demethylation), while the role of CYP3A4 significantly decreases (from 72% to 59% for 5-sulfoxidation, and from 78% to 47% for N-demethylation). The obtained results indicate that the catalysis of levomepromazine 5-sulfoxidation and N-demethylation in humans shows a strict CYP3A4 preference, especially at a therapeutic drug concentration. Hence pharmacokinetic interactions involving levomepromazine and CYP3A4 substrates (e.g. tricyclic antidepressants, calcium channel antagonists, macrolide antibiotics, testosterone), inhibitors (e.g. ketoconazole, erythromycin, SSRIs) or inducers (e.g. rifampicin, carbamazepine) are likely to occur.

Lung cancer risk in relation to nicotinic acetylcholine receptor, CYP2A6 and CYP1A1 genotypes in the Bangladeshi population

BackgroundCYP1A1, CYP2A6 and CHRNA5 are biologically plausible genes as risk factors for lung cancer but no studies have been reported in the Bangladeshi population. MethodsWe conducted this study to determine the prevalence and role of CYP1A1, CYP2A6 and CHRNA5 polymorphisms together with tobacco smoking in the development of lung cancer in Bangladesh. A case–control study was carried out on 106 lung cancer patients and 116 controls to investigate three allelic variants of the CYP1A1 gene—rs4646903, rs1048943 and rs1799814; 2 variants of CYP2A6 (CYP2A6*1B1, CYP2A6*4) and 1 variant of CHRNA5 (rs16969968) using Polymerase Chain Reaction Restriction Fragment Length Polymorphism. ResultsLung cancer risk was estimated as odds ratio (OR) and 95% confidence interval (CI) using unconditional logistic regression models adjusting for age, sex and smoking. A significantly elevated lung cancer risk was associated with heterozygous, mutant and combined heterozygous plus mutant variants of CYP1A1 rs4646903. A significant association was also found for heterozygous and heterozygous plus mutant variants of rs1048943 which was in linkage disequilibrium with rs4646903. The risk of lung cancer was decreased significantly in individuals carrying at least one CYP2A6 deletion (CYP2A6*4) allele. No association with lung cancer risk was found for CHRNA5 rs16969968. When stratified by smoking, the effects of CYP1A1 and CYP2A6 polymorphisms on lung cancer susceptibility were found to be significant only in heavy smokers who had smoked 40 pack years or more (54% of all cases) but no associations were seen for lighter smokers. No association was also found with any polymorphism in the non-smokers in this study. ConclusionsOur results indicate that the CYP1A1*2B allele (rs4646903 and rs1048943) is associated with an increased lung cancer risk and CYP2A6*4 is associated with a decreased lung cancer risk in the study population.

Role of CYP1A1 as a marker of teratogenesis using embryo limb bud micromass culture

Role of CYP1A1 as a marker of teratogenesis using embryo limb bud micromass culture

Role of CYP1A1 (T6235C) polymorphism and cigarette smoking in the development of coronary heart disease in Tunisian population

Coronary heart disease (CHD) is now the leading cause ofdeath worldwide: each year, 3.8 million men and 3.4 millionwomen die from CHD (World Health Organization 2008).The main causal risk factors of CHD include hypertension,dyslipidemia, diabetes mellitus and smoking. According tothe World Health Organization, tobacco use is the majorcause of many of the world’s top fatal diseases includingcardiovascular disease (World Health Organization 2008).Cigarette smoking can initiate atherogenesis, the major causeof developing CHD. There is evidence that mutagens suchas polycyclic aromatic hydrocarbons (PAHs) and aromaticamines found in tobacco smoke increase the development ofatherosclerotic lesions in experimental animals (Ramos andMoorthy 2005).Several reports have suggested that the metabolic acti-vation of PAHs by cytochrome P450 (CYPs), includingCYP1A1 is a necessary step for PAH-induced atheroscle-rosis. CYP1A1 is the main metabolizing enzyme of PAHs(Qiang and Lu 2007) that generates a highly electrophilicdiol-epoxide metabolite capable of creating DNA adducts(Jacquet

Дослідження можливої ролі поліморфізму генів CYP1A1, GSTT1, GSTM1, GSTP1, NAT2 і ADRB2 у розвитку бронхіальної астми у дітей

Дослідження можливої ролі поліморфізму генів CYP1A1, GSTT1, GSTM1, GSTP1, NAT2 і ADRB2 у розвитку бронхіальної астми у дітей

Bioactivation of aflatoxin B1 by turkey liver microsomes: responsible cytochrome P450 enzymes

1. A study was conducted to determine the cytochrome P450 enzymes responsible for the bioactivation of aflatoxin B1 into its epoxide form (AFBO) in turkey liver microsomes. 2. The strategies used included the measurement of prototype substrate activity for specific human P450s, use of selective inhibitors, determination of correlation between aflatoxin bioactivation and enzymatic activity of prototype substrates and the determination of immunoreactive proteins using antibodies against human P450s. 3. Enzymatic activity and immunoreactive proteins corresponding to the turkey orthologs CYP1A1, CYP1A2, CYP2A6 and CYP3A4 were detected, but not for the CYP2D6 ortholog. 4. The results of the inhibition and correlation studies strongly suggest that the turkey CYP2A6 ortholog and, to a lesser extent, the CYP1A1 ortholog, are involved in the bioactivation of aflatoxin B1 in turkey liver microsomes. 5. This is the first study reporting the role of CYP2A6 in the bioactivation of AFB1 in an avian species and the role of CYP1A1 in any species.

Exposure of human skin to benzo[a]pyrene: Role of CYP1A1 and aryl hydrocarbon receptor in oxidative stress generation

Exposure to benzo[a]pyrene (BaP) can induce inflammatory skin diseases and skin cancer, which are both associated to oxidative stress. BaP is known to bind with high specificity to the aryl hydrocarbon receptor (AhR), modifying the expression of CYP1A1, involved both in cancer and inflammation. While the current knowledge is based on murine skin and cell culture data, in this study human healthy skin has been treated with 5 μM BaP in conditions simulating occupational and environmental exposure. AhR and CYP1A1 expression was evaluated by Western blotting, which revealed their presence even in control untreated skin; both enzyme and receptor increased more than twofold after exposure to BaP. AhR expression level was lower than CYP1A1 in basal conditions and following induction. Oxidative stress was evaluated in terms of MTT reduction, protein peroxidation and reactive oxygen species (ROS) formation. A significant increase in ROS and carbonyl compound production, as well as reduced tissue viability have been determined by BaP. The results of this experiment indicate that BaP, an AhR agonist, can significantly increase receptor and CYP1A1 expression and induce oxidative stress in human skin, confirming the involvement of this pathway in the pathogenesis of tissue damage due to polycyclic aromatic hydrocarbons.

The role of CYP1A1 (Ile462Val) and CYP1B1 (Asn453Ser) polymorphisms in response to chemotherapy and survival in lung cancer patients

The role of CYP1A1 (Ile462Val) and CYP1B1 (Asn453Ser) polymorphisms in response to chemotherapy and survival in lung cancer patients

B408 Protective Role of CYP1A1*2A in the Development of Multiple Myeloma

B408 Protective Role of CYP1A1*2A in the Development of Multiple Myeloma