CYP19 Gene Research Articles

Differential Susceptibility to Benzo[a]pyrene Exposure during Gestation and Lactation in Mice with Genetic Variations in the Aryl Hydrocarbon Receptor and Cyp1 Genes.

Polycyclic aromatic hydrocarbons are ubiquitous air pollutants, with additional widespread exposure in the diet. PAH exposure has been linked to adverse birth outcomes and long-term neurological consequences. To understand genetic differences that could affect susceptibility following developmental exposure to polycyclic aromatic hydrocarbons, we exposed mice with variations in the aryl hydrocarbon receptor and the three CYP1 enzymes from gestational day 10 (G10) to weaning at postnatal day 25 (P25). We found unexpectedly high neonatal lethality in high-affinity AhrbCyp1b1(-/-) knockout mice compared with all other genotypes. Over 60% of BaP-exposed pups died within their first 5 days of life. There was a significant effect of BaP on growth rates in surviving pups, with lower weights observed from P7 to P21. Again, AhrbCyp1b1(-/-) knockout mice were the most susceptible to growth retardation. Independent of treatment, this line of mice also had impaired development of the surface righting reflex. We used high-resolution mass spectrometry to measure BaP and metabolites in tissues from both dams and pups. We found the highest BaP levels in adipose from poor-affinity AhrdCyp1a2(-/-) dams and identified three major BaP metabolites (BaP-7-OH, BaP-9-OH, and BaP-4,5-diol), but our measurements were limited to a single time point. Future work is needed to understand BaP pharmacokinetics in the contexts of gestation and lactation and how differential metabolism leads to adverse developmental outcomes.

Analysis of CYP17 gene polymorphism on increasing androstenedione levels in polycystic ovary syndrome women with obesity in Surabaya

Introduction: CYP17 gene polymorphism causes susceptibility, can interfere with the enzyme biosynthesis mechanism in steroidogenesis, and becomes a possible genetic factor for hyper-androgen in PCOS. The study aimed to analyze the relationship between CYP17 gene polymorphism and increased androstenedione levels in PCOS women with obesity. Methods: This study is an observational case-control analytic. The sample is 23 obese PCOS women and 23 obese non-PCOS women, using a purposive sampling technique. CYP17 gene polymorphism examination with PCR and RFLP. Examination of androstenedione hormone by ELISA. The examination results were tested using a logistic regression statistical test with α = 0.05, the hypothesis being accepted if p-value <0.005. Results: The study subjects were 20-30 years old, 50-60 kg body weight, with BMI more than 25%. The distribution of CYP17 gene genotypes in the case group was TC, 47.8%, while in the control group, it was TT, 100%, Chi-Square test on CYP17 gene polymorphism in PCOS and control groups showed significant differences (P 0.000). Wilcoxon-Mann Whitney test of androstenedione levels in cases compared to controls P = 0.000, eta CYP17 correlation test with androstenedione levels P = 0.061. Conclusion: There is a difference in CYP 17 gene polymorphism in obese PCOS women compared to obese non-PCOS women. Androstenedione levels are higher in PCOS women than in obese non-PCOS women and there is no association of CYP17 with Androstenedione levels in PCOS women with obesity.

CYP Gene Expression and In Vivo Biological Effects of Khat Ethanol Extract, Cathinone and Cathine in Caenorhabditis elegans

The significant influence of khat, cathinone, and cathine on appetite suppression, reproduction impairment, and inhibitory effects on CYPs enzyme activity is widely recognised, but much remains unknown about its mode of action. This study demonstrated that exposure to high doses of KEE, cathinone, cathine and sibutramine at 12.5, 1.8, 1.8 and 1.8 mg/ml showed the most visible reduction in pharyngeal pumping rate, respectively. C. elegans showed an anomalous dynamic of reproduction rate upon exposure to these compounds but overall, showed a reduced amount of progeny. KEE, cathinone, and cathine extended the lifespan of C. elegans as compared to sibutramine and control with survival rate increments of 59.5%, 43.3%, and 15%, respectively. Quantitative RT-PCR results were insignificant, but cyp-14A3, cyp-34A9, and cyp-35A2 across all treatments were upregulated, ranging from >1 to 3-fold as compared to control. cyp genes expression could be upregulated to enhance the metabolism of khat extract, cathinone, cathine, and sibutramine in C. elegans.

Delineating the role of single-nucleotide polymorphism of CYP19 gene on aromatase activity in South Indian women with polycystic ovary syndrome

BackgroundPolycystic ovary syndrome is a common multifactorial endocrinopathy disorder affecting 5–15% of reproductive women worldwide. The CYP19 gene encodes key enzyme aromatase involved in androgen-to-estrogen conversion which plays a crucial role in the pathophysiology of the syndrome. Very few studies have been done in the Indian population; hence, we investigated whether CYP19 gene rs2414096 SNP is associated with PCOS and hyperandrogenism susceptibility in Karnataka women. MethodsThree-hundred subjects including 150 PCOS and 150 age-matched controls were involved in the current case–control study. Sex hormones and biochemical estimation were performed by ELISA. Sanger sequencing and PCR–RFLP were used to genotype the SNP rs2414096. Genotypic-phenotypic association was studied. Statistical analysis was performed. ResultsThe GG genotype was more common in patients, while the GA genotype was more common in control women. LH/FSH was significantly increased in GG genotype in PCOS when compared with AA and GA genotypes. Variations of CYP19 rs2414096 were not statistically significant with PCOS. ConclusionCYP19 rs2414096 polymorphism was not associated with PCOS; however, the homozygous wild GG genotype may exhibit reduced aromatase activity with subsequent hyperandrogenism implicating endocrine abnormalities.

Omics shed light on the mechanisms of petroleum‐contaminated soil remediation: When biochar meets nitrogen

AbstractDecontamination of oil‐affected soil is an urgent worldwide issue. In this study, a microcosm experiment was conducted to explore the effect of combined utilization of urea and biochar on oil‐contamination remediation in an eastern China oil‐field soil and explored their impact on soil physicochemical properties, organic pollutants degrading‐related enzyme and functional genes, microbiome, and metabolome. Then, a pot experiment was conducted to verify the impact of the remediation experiment. Results showed that a combined application of biochar and nitrogen reduced 78.6% of total petroleum hydrocarbons in soil. Combined treatment enhanced soil dehydrogenase and catalase activities, alkB, and CYP gene abundances relative to Control. Moreover, nitrogen input reduced soil microbial α‐diversity, while improving the relative abundances of Alcanivorax and Pseudogym. In addition, the pathways of glyoxylate and dicarboxylate metabolism, naphthalene and anthracene degradation, butanoate metabolism, pyruvate metabolism, and glycolysis or gluconeogenesis were up‐regulated in combined treatment relative to Control. Besides, both biochar and nitrogen addition can increase the number of edges and clustering coefficient of the microbial network, and improve the network robustness. The pot experiment showed that combined treatments enhanced ryegrass shoot length, root length, and biomass by 57.8%, 38.5%, and 42.8%, respectively. Overall, this study proved the feasibility of combined biochar and urea co‐application in remedying oil‐contaminated soil and shed light on the inner mechanism.

PROSPECTIVE RANDOMIZED STUDY USING PHARMACOGENETICS TO OPTIMIZE PERIOPERATIVE PAIN MANAGEMENT AFTER TOTAL KNEE ARTHROPLASTY

AbstractIntroductionAdverse reactions to pain medication and pain can delay discharge after outpatient knee arthroplasty (TKA). Pharmacogenomics is an emerging tool that might help reduce adverse events by tailoring medication use based on known genetic variations in the CYP genes determining drug metabolism. This study was undertaken to evaluate whether pre-operative pharmacogenomic testing could optimize peri-operative pain management in patients undergoing total knee arthroplasty (TKA).MethodsThis prospective, randomized study was performed in adults undergoing primary TKA. Patients in the experimental group underwent pre-operative pharmacogenomic evaluation and medication adjustments. Medications were not optimized for control patients. The Overall Benefit of Analgesic Score (OBAS) at 24 hours post-op was the primary outcome. Postoperative pain scores (VAS scale), total opioid use, time in recovery, and time to discharge were also compared.Results76 patients enrolled. 93% of patients had a poor-intermediate phenotype for at least one of four CYP genes. OBAS did not differ significantly between the two groups (4.2 control vs. 4.7 experimental; 95% CI −1.1 to 2.1) and was below the minimum clinically important difference of 2.0 points. Furthermore, there were no differences in any OBAS subscale including pain, satisfaction, or nausea. There were no differences in time in the recovery area or to discharge from hospital, or narcotic use.ConclusionsDespite many patients having a poor-intermediate phenotype for a CYP gene, pharmacogenomic testing prior to TKA and medication adjustment did not improve anesthesia or pain management outcomes, time to discharge or mean total opioid use after surgery.

Relation between HLA and copy number variation of steroid 21-hydroxylase in a Swedish cohort of patients with autoimmune Addison's disease.

Autoantibodies against the adrenal enzyme 21-hydroxylase is a hallmark manifestation in autoimmune Addison's disease (AAD). Steroid 21-hydroxylase is encoded by CYP21A2, which is located in the HLA region together with the highly similar pseudogene CYP21A1P. A high level of copy number variation is seen for the two genes, and therefore we asked if genetic variation of the CYP21 genes is associated with AAD. Using next-generation DNA sequencing, we estimated the copy number of CYP21A2 and CYP21A1P together with HLA alleles in 479 Swedish patients with AAD and autoantibodies against 21-hydroxylase, and in 1,393 healthy controls. With 95% of individuals carrying two functional 21-hydroxylase genes, no difference in CYP21A2 copy number was found when comparing patients and controls. In contrast, we discovered a lower copy number of the pseudogene CYP21A1P among AAD patients (p = 5 x 10-44) together with associations of additional nucleotide variants in the CYP21 region. However, the strongest association was found for HLA-DQB1*02:01 (p = 9 x 10-63), which in combination with the DRB1*04:04-DQB1*03:02 haplotype imposed the greatest risk of AAD. We identified strong associations between copy number variants in the CYP21 region and risk of AAD, although these associations most likely are due to linkage disequilibrium with disease-associated HLA class II alleles.

Transcriptome-Wide Identification of Cytochrome P450s and GSTs from Spodoptera exigua Reveals Candidate Genes Involved in Camptothecin Detoxification

The application of camptothecin (CPT) and its derivatives to control insect pests has generated significant interest. This study investigated the enzymatic response of cytochrome P450 monooxygenase (CYP) and glutathione S-transferase (GST) genes in the fat body cells of Spodoptera exigua after 10 μM CPT treatment. Additionally, we examined the effects of CPT on the growth and development of S. exigua larvae and detected the relative expression levels of selected CYP and GST genes during the CPT treatment period. Twenty-one CYP and 17 GST genes were identified from the fat body cells of S. exigua by comparative transcriptomic analyses. The relative expression of ten CYP and seven GST genes changed significantly, which suggested that these CPYs and GSTs may be involved in CPT metabolism. During exposure to CPT for 10 days, the development of S. exigua larvae was delayed and was characterized by weight inhibition and a prolonged period of development. The relative expression levels of the selected four CYP genes, CYP9A27, CYP9A186, CYP337B5, CYP321A8, and one GST gene, GSTe7, were significantly changed by CPT treatment compared to the control group. These generated data provide a basis for identifying the CPT metabolism/detoxification genes of S. exigua at the molecular level.

Genital stones: Radiological, histopathological, ultrastructural, and molecular analysis in rooster

Epididymal lithiasis, characterized by the formation of stones in the epididymis, has been associated with a decline in fertility in roosters. This study aimed to investigate the reproductive performance, ultrastructural characteristics, and expression of aromatase cytochrome P450 (CYP19) and aquaporin 9 (AQP9) in aged broiler breeder roosters affected by epididymal lithiasis. X-ray analysis confirmed the presence of genital stones in both the epididymis and testicular tissue regions. While there was a significant decrease in sperm concentration in the affected roosters compared to non-affected roosters, no significant differences were observed in total and progressive sperm motility between the two groups. Furthermore, the affected roosters exhibited significant abnormalities in semen parameters, except for sperm concentration and morphology. Transmission electron microscopy (TEM) revealed the depletion and deciliation of ciliated cells in the distal efferent ductules of the epididymis in affected roosters. Additionally, the expression of CYP19 and AQP9 was found to be increased in the epididymal region of affected roosters. Notably, we report the presence of testicular stones for the first time in this study, in addition to epididymal stones. Considering the male reproductive tract lesions observed, we propose the term “genital stones” to describe these conditions. Moreover, our findings suggest that the overexpression of AQP9, which is associated with a high copy number of the CYP19 gene in the epididymal region of affected aged roosters, may contribute to the formation of genital stones by promoting increased reabsorption of fluids in the epididymis. The condensation of epididymal duct contents and reduction in the population of ciliated cells further impairs semen movement and can lead to the blockage of extra-testicular ducts, resulting in the low fertility syndrome observed in aged roosters.

Effect of polymorphisms CYP17 (rs743572), SOD2 (rs4880) and CAT (rs1001179) on hormonal profile and redox status of blood serum and follicular fluid in patients with polycystic ovary syndrome

Polycystic Ovary syndrome (PCOS) is a heterogeneous disease, and its pathophysiology is quite complex. Hyperandrogenism, insulin resistance and recently oxidative stress are considered the main causes of initiating and developing the disease, they act synergistically and stimulate each other in a vicious cycle. Our study was aimed at investigation the relationship between polymorphisms in the genes CYP17 (rs743572), SOD2 (rs4880), and CAT (rs1001179) and the risk of PCOS. As well as to establish the relationship of polymorphic markers with the development of oxidative stress and a violation of the hormonal profile of blood serum and follicular fluid in PCOS. Our genotyping analysis showed that polymorphisms in CYP17 (rs743572) and SOD2 (rs4880), but not CAT (rs1001179) might be risk factors for PCOS development, since the presence of at least one mutant allele of rs743572 or rs4880 increases the risk of developing the syndrome. We found an association between LH and estradiol levels in the serum and the polymorphic variants of CYP17 (rs743572) and SOD2 (rs4880), respectively in PCOS patients. Furthermore, our results demonstrate a significant increase in oxidative stress with a decrease in SOD and CAT activity in the follicular fluid of PCOS patients.

Galactosylation of rat natural scaffold for MSC differentiation into hepatocyte-like cells: A comparative analysis of 2D vs. 3D cell culture techniques

The liver plays a crucial role in drug detoxification, and the main source of liver transplants is brain-dead patients. However, the demand for transplants exceeds the available supply, leading to controversies in selecting suitable candidates for acute liver diseases. This research aimed to differentiate mesenchymal stem cells (MSCs) into hepatocyte-like cells using galactosylated rat natural scaffolds and comparing 2-D and 3-D cell culture methods. The study involved isolating and culturing Wharton's jelly cells from the umbilical cord, examining surface markers and adipogenic differentiation potential of MSCs, and culturing mesenchymal cells on galactosylated scaffolds. The growth and proliferation of stem cells on the scaffolds were evaluated using the MTT test, and urea synthesis was measured in different culture environments. Changes in gene expression were analyzed using real-time PCR. Flow cytometry results confirmed the presence of specific surface antigens on MSCs, indicating their identity, while the absence of a specific antigen indicated their differentiation into adipocytes. The MTT test revealed higher cell attachment to galactosylated scaffolds compared to the control groups. Urea secretion was observed in differentiated cells, with the highest levels in cells cultured on galactosylated scaffolds. Gene expression analysis showed differential expression patterns for OCT-4, HNF1, ALB, AFP, and CYP genes under different conditions. The findings indicated that hepatocyte-like cells derived from 3D cultures on galactosylated scaffolds exhibited superior characteristics compared to cells in other culture conditions. These cells demonstrated enhanced proliferation, stability, and urea secretion ability. The study also supported the differentiation potential of MSCs derived from Wharton's jelly umbilical cord into liver-like cells.

Pharmacogenomics and the Concept of Personalized Medicine for the Management of Hypertension

Pharmacogenomics and the Concept of Personalized Medicine for the Management of Hypertension

Functional roles of two novel P450 genes in the adaptability of Conogethes punctiferalis to three commonly used pesticides.

Introduction: Insect cytochrome P450 (CYP450) genes play important roles in the detoxification and metabolism of xenobiotics, such as plant allelochemicals, mycotoxins and pesticides. The polyphagous Conogethes punctiferalis is a serious economic pest of fruit trees and agricultural crops, and it shows high adaptability to different living environments. Methods: The two novel P450 genes CYP6CV1 and CYP6AB51 were identified and characterized. Quantitative real-time PCR (qRT-PCR) technology was used to study the expression patterns of the two target genes in different larval developmental stages and tissues of C. punctiferalis. Furthermore, RNA interference (RNAi) technology was used to study the potential functions of the two P450 genes by treating RNAi-silenced larvae with three commonly used pesticides. Results: The CYP6CV1 and CYP6AB51 genes were expressed throughout various C. punctiferalis larval stages and in different tissues. Their expression levels increased along with larval development, and expression levels of the two target genes in the midgut were significantly higher than in other tissues. The toxicity bioassay results showed that the LC50 values of chlorantraniliprole, emamectin benzoate and lambda-cyhalothrin on C. punctiferalis larvae were 0.2028μg/g, 0.0683μg/g and 0.6110mg/L, respectively. After treating with different concentrations of chlorantraniliprole, emamectin benzoate and lambda-cyhalothrin (LC10, LC30, LC50), independently, the relative expressions of the two genes CYP6CV1 and CYP6AB51 were significantly induced. After the dsRNA injection, the expression profiles of the two CYP genes were reduced 72.91% and 70.94%, respectively, and the mortality rates of the larvae significantly increased when treated with the three insecticides independently at LC10 values. Discussion: In the summary, after interfering with the CYP6CV1 and CYP6AB51 in C. punctiferalis, respectively, the sensitivity of C. punctiferalis to chlorantraniliprole, emamectin benzoate and lambda-cyhalothrin was significantly increased, indicating that the two CYP6 genes were responsible for the adaptability of C. punctiferalis to the three chemical insecticides in C. punctiferalis. The results from this study demonstrated that CYP6CV1 and CYP6AB51 in C. punctiferalis play crucial roles in the detoxification of chlorantraniliprole, emamectin benzoate and lambda-cyhalothrin.

Human induced pluripotent stem cell-derived liver-on-a-chip for studying drug metabolism: the challenge of the cytochrome P450 family.

The liver is the primary organ responsible for the detoxification and metabolism of drugs. To date, a lack of preclinical models that accurately emulate drug metabolism by the human liver presents a significant challenge in the drug development pipeline, particularly for predicting drug efficacy and toxicity. In recent years, emerging microfluidic-based organ-on-a-chip (OoC) technologies, combined with human induced pluripotent stem cell (hiPSC) technology, present a promising avenue for the complete recapitulation of human organ biology in a patient-specific manner. However, hiPSC-derived organoids and liver-on-a-chip models have so far failed to sufficiently express cytochrome P450 monooxygenase (CYP450) enzymes, the key enzymes involved in first-pass metabolism, which limits the effectiveness and translatability of these models in drug metabolism studies. This review explores the potential of innovative organoid and OoC technologies for studying drug metabolism and discusses their existing drawbacks, such as low expression of CYP450 genes. Finally, we postulate potential approaches for enhancing CYP450 expression in the hope of paving the way toward developing novel, fully representative liver drug-metabolism models.

Nontarget Site-Based Resistance to Fenoxaprop-P-ethyl and Candidate Genes Involved in Alopecurus japonicus

Nontarget-site resistance (NTSR) is a complex multigenic trait that is associated with the potential mechanisms of herbicide resistance which pose a serious threat to global crop protection. However, the NTSR mechanisms of Alopecurus japonicus, a malignant weed infesting wheat fields, are less characterized. In this study, we used RNA-sequencing transcriptome and enzyme activity detection to investigate the NTSR mechanisms and candidate genes involved in fenoxaprop-P-ethyl (FE) in a previously identified resistant population compared to the sensitive population of A. japonicus. Transcriptome analysis identified nine upregulated genes, which were constitutively overexpressed and upregulated by FE application in the resistant population, and the results were validated using quantitative real-time PCR. These genes including one cytochrome P450 monooxygenase (P450) gene (CYP75B4), one ATP-binding cassette (ABC) transporter gene (ABCG36), one laccase (LAC) gene (LAC15), one 9-cis-epoxycarotenoid dioxygenase (NCED) gene (NCED5), two purple acid phosphatase (PAP) genes (PAP4, PAP15), one sucrose phosphate synthase (SPS) gene (SPS3), one protein related to disease resistance gene (RGA3) and one immune protein gene (R1B-17). The activity assay of LAC, NCED, PAP and SPS revealed that the activities of these enzymes in the resistant population were significantly higher than those in the sensitive population at 0 h and after FE application at 12 h, 24 h and 72 h. Nevertheless, whether LAC, NCED, PAP and SPS genes were involved in herbicide metabolism needs to be further validated. Our results revealed that CYP, ABC transporter and LAC genes may participate in A. japonicus resistance. These genes identified in the present study provide new insights into the resistance mechanism of weeds in response to herbicide. Our study also implies the complexity of the NTSR mechanisms of weeds.

A Comparative Genomic and Phylogenetic Investigation of the Xenobiotic Metabolism Enzymes of Cytochrome P450 in Elephants Shows Loss in CYP2E and CYP4A.

Cytochrome P450 is an important enzyme that metabolizes a variety of chemicals, including exogenous substances, such as drugs and environmental chemicals, and endogenous substances, such as steroids, fatty acids, and cholesterol. Some CYPs show interspecific differences in terms of genetic variation. As little is known about the mechanisms of elephant metabolism, we carried out a comparative genomic and phylogenetic analysis of CYP in elephants. Our results suggest that elephant CYP genes have undergone independent duplication, particularly in the CYP2A, CYP2C, and CYP3A genes, a unique cluster specific to elephant species. However, while CYP2E and CYP4A were conserved in other Afrotheria taxa, their decay in elephants resulted in genetic dysfunction (pseudogene). These findings outline several remarkable characteristics of elephant CYP1-4 genes and provide new insights into elephant xenobiotic metabolism. Further functional investigations are necessary to characterize elephant CYP, including expression patterns and interactions with drugs and sensitivities to other chemicals.

The velvet family proteins mediate low resistance to isoprothiolane in Magnaporthe oryzae.

Isoprothiolane (IPT) resistance has emerged in Magnaporthe oryzae, due to the long-term usage of IPT to control rice blast in China, yet the mechanisms of the resistance remain largely unknown. Through IPT adaptation on PDA medium, we obtained a variety of IPT-resistant mutants. Based on their EC50 values to IPT, the resistant mutants were mainly divided into three distinct categories, i.e., low resistance (LR, 6.5 ≤ EC50 < 13.0 μg/mL), moderate resistance 1 (MR-1, 13.0 ≤ EC50 < 25.0 μg/mL), and moderate resistance 2 (MR-2, 25.0 ≤ EC50 < 35.0 μg/mL). Molecular analysis of MoIRR (Magnaporthe oryzae isoprothiolane resistance related) gene demonstrated that it was associated only with the moderate resistance in MR-2 mutants, indicating that other mechanisms were associated with resistance in LR and MR-1 mutants. In this study, we mainly focused on the characterization of low resistance to IPT in M. oryzae. Mycelial growth and conidial germination were significantly reduced, indicating fitness penalties in LR mutants. Based on the differences of whole genome sequences between parental isolate and LR mutants, we identified a conserved MoVelB gene, encoding the velvet family transcription factor, and genetic transformation of wild type isolate verified that MoVelB gene was associated with the low resistance. Based on molecular analysis, we further demonstrated that the velvet family proteins VelB and VeA were indispensable for IPT toxicity and the deformation of the VelB-VeA-LaeA complex played a vital role for the low IPT-resistance in M. oryzae, most likely through the down-regulation of the secondary metabolism-related genes or CYP450 genes to reduce the toxicity of IPT.

Aliens in the CYPome of the black fungus gnat, Bradysia coprophila

The diverse cytochrome P450 enzymes of insects play essential physiological roles and also play important roles in the metabolism of environmental chemicals such as insecticides. We manually curated the complement of P450 (CYP) genes, or CYPome, of the black fungus gnat, Bradysia (Sciara) coprophila (Diptera, Sciaroidea), a species with a variable number of chromosomes. This CYPome carries two types of “alien” P450 genes. The first type of alien P450s was found among the 163 CYP genes of the core genome (autosomes and X). They consist of 28 sequences resulting from horizontal gene transfer, with closest sequences not found in insects, but in other arthropods, often Collembola. These genes are not contaminants, because they are expressed genes with introns, found in synteny with regular dipteran genes, also found in B. odoriphaga and B. hygida. Two such “alien” genes are representatives of CYP clans not otherwise found in insects, a CYP53 sequence related to fungal CYP53 genes, and a CYP19-like sequence similar to some collembolan sequences but of unclear origin. The second type of alien P450s are represented by 99 sequences from germline-restricted chromosomes (GRC). While most are P450 pseudogenes, 33 are apparently intact, with half being more closely related to P450s from Cecidomyiidae than from Sciaridae, thus supporting the hypothesis of a cross-family hybridization origin of the GRC.

CYP metabolic pathway related gene polymorphism increases the risk of embolic and atherothrombotic stroke and vulnerable carotid plaque in southeast China

ObjectiveTo investigate the association of CYP metabolic pathway-related genetic polymorphisms with the susceptibility to ischemic stroke and stability of carotid plaque in southeast China. MethodsWe consecutively enrolled 294 acute ischemic stroke patients with carotid plaque and 282 controls from Wenling First People's Hospital. The patients were divided into the carotid vulnerable plaque group and stable plaque group according to the results of carotid B-mode ultrasonography. Polymorphisms of CYP3A5 (G6986A, rs776746), CYP2C9*2 (C430T, rs1799853), CYP2C9*3 (A1075C, rs1057910), and EPHX2 (G860A, rs751141) were determined using polymerase chain reaction and mass spectrometry analysis. ResultsEPHX2 GG may reduce the susceptibility to ischemic stroke (OR = 0.520, 95% CI: 0.288 ∼ 0.940, P = 0.030) and AA+AG may increase the risk for ischemic stroke (OR = 1.748, 95% CI: 1.001 ∼ 3.052, P = 0.050). The distribution of CYP3A5 genotypes showed significant differences between the vulnerable plaque and stable plaque groups (P = 0.026). Multivariate logistic regression analysis found that CYP3A5 GG could reduce the risk of vulnerable plaques (OR = 0.405, 95% CI: 0.178 ∼ 0.920, P = 0.031). ConclusionEPHX2 G860A polymorphism may reduce the stroke susceptibility, while other SNPs of CYP genes are not associated with ischemic stroke in southeast China. Furthermore CYP3A5 polymorphism was related with carotid plaque instability.

Zearalenone Does Not Show Genotoxic Effects in the Drosophila melanogaster Wing Spot Test, but It Induces Oxidative Imbalance, Development, and Fecundity Alterations

Zearalenone (ZEN) is a non-steroidal mycoestrogen produced by the Fusarium genus. ZEN and its metabolites compete with 17-beta estradiol for cytosolic estrogen receptors, causing reproductive alterations in vertebrates. ZEN has also been associated with toxic and genotoxic effects, as well as an increased risk for endometrial adenocarcinomas or hyperplasia, breast cancer, and oxidative damage, although the underlying mechanisms remain unclear. Previous studies have monitored cellular processes through levels of transcripts associated with Phase I Xenobiotic Metabolism (Cyp6g1 and Cyp6a2), oxidative stress (hsp60 and hsp70), apoptosis (hid, grim, and reaper), and DNA damage genes (Dmp53). In this study, we evaluated the survival and genotoxicity of ZEN, as well as its effects on emergence rate and fecundity in Drosophila melanogaster. Additionally, we determined levels of reactive oxygen species (ROS) using the D. melanogaster flare and Oregon R(R)-flare strains, which differ in levels of Cyp450 gene expression. Our results showed that ZEN toxicity did not increase mortality by more than 30%. We tested three ZEN concentrations (100, 200, and 400 μM) and found that none of the concentrations were genotoxic but were cytotoxic. Taking into account that it has previously been demonstrated that ZEN administration increased hsp60 expression levels and apoptosis gene transcripts in both strains, the data agree with an increase in ROS and development and fecundity alterations. Since Drosophila lacks homologous genes for mammalian estrogen receptors alpha and beta, the effects of this mycotoxin can be explained by a mechanism different from estrogenic activity.