CYP19 Gene Research Articles

Frequency of Important CYP450 Enzyme Gene Polymorphisms in the Iranian Population in Comparison with Other Major Populations: A Comprehensive Review of the Human Data.

Genetic polymorphisms in cytochrome P450 genes can cause alteration in metabolic activity of clinically important medicines. Thus, single nucleotide variants (SNVs) and copy number variations (CNVs) in CYP genes are leading factors of drug pharmacokinetics and toxicity and form pharmacogenetics biomarkers for drug dosing, efficacy, and safety. The distribution of cytochrome P450 alleles differs significantly between populations with important implications for personalized drug therapy and healthcare programs. To provide a meta-analysis of CYP allele polymorphisms with clinical importance, we brought together whole-genome and exome sequencing data from 800 unrelated individuals of Iranian population (100 subjects from 8 major ethnics of Iran) and 63,269 unrelated individuals of five major human populations (EUR, AMR, AFR, EAS and SAS). By integrating these datasets with population-specific linkage information, we evolved the frequencies of 140 CYP haplotypes related to 9 important CYP450 isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5) giving a large resource for major genetic determinants of drug metabolism. Furthermore, we evaluated the more frequent Iranian alleles and compared the dataset with the Caucasian race. Finally, the similarity of the Iranian population SNVs with other populations was investigated.

Effect of Neonicotinoids on Bacterial Symbionts and Insecticide-Resistant Gene in Whitefly, Bemisia tabaci.

Simple SummaryThe silverleaf whitefly (B. tabaci) is an important agricultural pest damaging several agricultural and horticultural crops worldwide. Keeping in mind the status of insecticide overuse, the current experiment was designed to evaluate the sensitivity of B. tabaci towards imidacloprid and thiamethoxam (two popularly used neonicotinoids in India). The lab population of B. tabaci was found to be more susceptible to thiamethoxam compared to imidacloprid. qPCR studies revealed a higher expression of insecticide-resistant genes, CYP6CM1 and CYP6CX1, after imidacloprid treatment that might be responsible for increased resistance to insecticides. Our results also put forward the different interactions between symbionts and insecticide resistance. qPCR studies revealed thiamethoxam-treated B. tabaci populations harbored a higher amount of primary endosymbiont Portiera and a lower amount of secondary symbiont Rickettsia.The silverleaf whitefly, Bemisia tabaci (Gennadius, Hemiptera: Aleyrodidae), is a major threat to field and horticultural crops worldwide. Persistent use of insecticides for the management of this pest is a lingering problem. In the present study, the status of sensitivity of B. tabaci to two neonicotinoids, imidacloprid and thiamethoxam, was evaluated. The expression pattern of two cytochrome P450 (cyp) genes and changes in the relative amount of symbionts in insecticide-treated B. tabaci were also assessed. Quantitative PCR (qPCR) studies indicate that the CYP6CM1 and CYP6CX1 genes were always expressed higher in imidacloprid-treated whitefly, suggesting a correlation between gene expression and the insect’s ability to detoxify toxic compounds such as insecticides. In addition, the thiamethoxam-treated population harbored higher Portiera and lower Rickettsia titers, whereas the imidacloprid-treated population harbored more Rickettsia at different time intervals. Interestingly, we also examined that an increase in exposure to both the insecticides resulted in a reduction in the mutualistic partners from their insect host. These differential responses of endosymbionts to insecticide exposure imply the complex interactions among the symbionts inside the host insect. The results also provide a deeper understanding of the molecular mechanism of resistance development that might be useful for formulating effective management strategies to control B. tabaci by manipulating symbionts and detoxifying genes.

Protective effects of pretreatment with Fe2+, Cu2+, and Rb+ on phoxim poisoning in silkworm, Bombyx mori

BackgroundPhoxim is a widely used organophosphorus pesticide in agriculture. People are paying more and more attention to its toxicity. At present, there is no appropriate way to solve the phoxim poisoning of silkworm, which severely affected the development of sericulture. Fe2+, Cu2+, Rb+ exerted their biological effects through various forms in vivo. MethodsTo evaluate the effect of Fe2+/Cu2+/Rb+ on phoxim poisoning in silkworm, Bombyx mori were treated with fresh mulberry leaves soaked in 2.5 mg/L phoxim for 2 min with 50 mg/L FeCl2, 150 mg/L CuCl2, or 0.5 mg/L RbCl from 5 days of the fifth-instar silkworm. ResultsFe2+, Cu2+, and Rb+ pretreatments significantly inhibited the phoxim-induced reduction of survival rate and alleviated the phoxim-induced poisoning symptoms. The protective effects of Fe2+, Cu2+, and Rb+ on phoxim poisoning might be due to their enhancement of superoxide dismutase (SOD), catalase (CAT), and carboxylesterase (CarE) in the hemolymph and fat body of silkworm. This enhancement might reduce reactive oxygen species (ROS) accumulation and oxidative stress (OS) caused by phoxim poisoning. Thereby it reduced the damage to silkworm tissues and cells. ConclusionsThese results showed that Fe2+, Cu2+, and Rb+ treatments protected the silkworm from phoxim poisoning by directly enhancing the activity of SOD, CAT, and CarE enzymes and reducing oxidative stress, but not dependent on the high expression of CYP genes. The use of Fe2+, Cu2+, and Rb+ to enhance the activity of SOD, CAT, and CarE enzymes may be an underlying effective way to solve phoxim poisoning in the silkworm industry.

Effect of 5-fluorouracil on mRNA expression of drug metabolizing enzyme and transporter genes in human hepatoma cell lines.

Fluoropyrimidines such as 5-fluorouracil (5-FU) are well known to have drug-drug interactions with anticoagulant medications such as warfarin. This study investigated the mRNA expression of pharmacokinetic (PK)-related genes in response to 5-FU using the hepatocarcinoma cell lines after examining relevant gene expression via RNA sequencing. We used HepaRG cells for 5-FU treatment analysis because these cells displayed PK-related gene expression. 5-FU exposure significantly reduced cytochrome P450 3A4 (CYP3A4) mRNA expression. Additionally, the mRNA expression of nuclear receptor subfamily 1 group I member 2 (also known as pregnane X receptor), a nuclear receptor transcription factor that promotes the expression of many CYP genes, was also decreased in HepaRG cells following 5-FU treatment. The mRNA expressions of the CYP2B6 and ATP-binding cassette transporter genes were decreased after 5-FU treatment. This study revealed that 5-FU treatment reduced PK-related gene expression in HepaRG cells. These findings should be useful for further drug-drug interaction research.

Expression of reproductive-related genes and changes in oocyte maturation of goldfish broodstock (Carassius auratus) following injection of different exogenous kisspeptins.

Kisspeptin, upstream of the hypothalamic-pituitary-gonadal axis, play an essential role in the reproductive process. In the present study, the effect of different types of kisspeptin, including goldfish (Carassiusauratus) kiss1 kisspeptin (Kiss1), human kisspeptin (Hkiss) and their combination (Kiss1+H) on the reproductive-related genes (kiss1, Kissr and Cyp19) of adult female goldfish was investigated in comparison with Ovaprim (a synthetic GnRH hormone). Kiss1 and Hkiss were synthesized using a solid-phase synthesis approach. Peptides were injected at a dose of 100μg/kg body weight. The brain and ovarian tissues of samples were separated for histological studies 24hr post-injection. The expression of the kiss1, Kissr and Cyp19 genes was measured by RT-PCR. The results showed a significant increase in expression of the reproductive-related genes. Histological analysis revealed higher number of mature oocytes in kisspeptin treated groups compare to other ones. In conclusion, Hkiss and Kiss1+H are the most effective peptides in oocyte maturation and expression of reproductive-related genes. In addition, it seems that kisspeptins in other domestic animals can be used to stimulate the hypothalamus-pituitary-gonadal axis.

Genotypic spectrum of 21-hydroxylase deficiency in an endogamous population.

Congenital adrenal hyperplasia (CAH) due to autosomal recessive 21-hydroxylase deficiency (21-OHD) is caused by defects in the CYP21 (CYP21A2) gene. Several mutations have been identified in the CYP21 (CYP21A2) gene of patients with 21-OHD. We aimed at determining the frequency of these mutations among a group of Egyptian patients and studying the genotype-phenotype correlation. Forty-seven patients with CAH due to 21-OHD from 42 different families diagnosed by clinical and hormonal evaluation and classified accordingly into salt wasting (SW) and simple virilizing (SV) phenotypes were enrolled. Their ages ranged between 1.78 and 18.99years. Molecular analysis of the CYP21 (CYP21A2) gene was performed for the detection of eleven common mutations: P30L, I2 splice (I2 G), Del 8bp E3 (G110del8nt), I172N, cluster E6 (I236N, V237E, M239K), V281L, L307 frameshift (F306 + T), Q318X, R356W, P453S, R483P by polymerase chain reaction (PCR) and reverse hybridization. Disease-causing mutations were identified in 47 patients, 55.31% of them were compound heterozygous. The most frequent mutations were I2 splice (25.43%), followed by cluster E6 (16.66%) and P30L (15.78%). Two point mutations (P453S, R483P) were not identified in any patient. In the SW patients, genotypes were more compatible with their phenotypes. Molecular characterization should be considered along with clinical and biochemical diagnosis of CAH since it could confirm the diagnosis, outline the treatment strategy and morbidity, and ensure proper genetic counseling.

Protocol for a pharmacogenetic study of antidepressants: characterization of drug-metabolizing profiles of cytochromes CYP2D6 and CYP2C19 in a Sardinian population of patients with major depressive disorder.

The effectiveness of antidepressants shows high interindividual variability ranging from full symptomatologic remission to treatment-resistant depression. Many factors can determine the variation in the clinical response, but a fundamental role is played by genetic variation within the genes encoding for the enzymes most involved in the metabolism of antidepressant drugs: the CYP2D6 and CYP2C19 isoforms of the cytochrome P450 system. This study is poised to clarify whether the different metabolizing phenotypes related to CYP2D6 and CYP2C19 could have an impact on the clinical efficacy of antidepressants and whether the frequency of these phenotypes of metabolization shows differences in the population of Sardinian patients compared to other Caucasian populations. The sample is being recruited from patients followed-up and treated at the Psychiatric Unit of the Department of Medical Science and Public Health, University of Cagliari and the University Hospital Agency of Cagliari (Italy). The study design includes three approaches: (1) a pharmacogenetic analysis of 80 patients diagnosed with MDD resistant to antidepressant treatment compared to 80 clinically responsive or remitted patients; (2) a prospective arm (N = 30) of the study where we will test the impact of genetic variation within the CYP2D6 and CYP2C19 genes on clinical response to antidepressants and on their serum levels and (3) the assessment of the socio-economic impact of antidepressant therapies, and estimation of the cost-effectiveness of the pharmacogenetic test based on CYP genes.

Physiological role of CYP17A1-like in cadmium detoxification and its transcriptional regulation in the Pacific oyster, Crassostrea gigas

Cadmium (Cd) is one of the most harmful heavy metals due to its persistence and bioaccumulation through the food chains, posing health risks to human. Oysters can bioaccumulate and tolerate high concentrations of Cd, providing a great model for studying molecular mechanism of Cd detoxification. In a previous study, we identified two CYP genes, CYP17A1-like and CYP2C50, that were potentially involved in Cd detoxification in the Pacific oyster, Crassostrea gigas. In this work, we performed further investigations on their physiological roles in Cd detoxification through RNA interference (RNAi). After injection of double-stranded RNA (dsRNA) into the adductor muscle of oysters followed by Cd exposure for 7 days, we observed that the expressions of CYP17A1-like and CYP2C50 in interference group were significantly suppressed on day 3 compared with control group injected with PBS. Moreover, the mortality rate and Cd content in the CYP17A1-like dsRNA interference group (dsCYP17A1-like) was significantly higher than those of the control on day 3. Furthermore, the activities of antioxidant enzymes, including SOD, CAT, GST, were significantly increased in dsCYP17A1-like group, while were not changed in dsCYP2C50 group. More significant tissue damage was observed in gill and digestive gland of oysters in RNAi group than control group, demonstrating the critical role of CYP17A1-like in Cd detoxification. Dual luciferase reporter assay revealed three core regulatory elements of MTF-1 within promoter region of CYP17A1-like, suggesting the potential transcriptional regulation of CYP17A1-like by MTF-1 in oysters. This work demonstrated a critical role of CYP17A1-like in Cd detoxification in C. gigas and provided a new perspective toward unravelling detoxification mechanisms of bivalves under heavy metal stress.

Negative cross-resistance to clomazone in imazethapyr-resistant Echinochloa crus-galli caused by increased metabolization

Herbicide resistance is frequently reported in E. crus-galli globally with target and non-target site resistance mechanism to acetolactate synthase (ALS)-inhibiting herbicides. However, resistance to certain herbicides can result in increased sensitivity to other herbicides, a phenomenon called negative cross-resistance. The objective of this study is to identify the occurrence of negative cross-resistance (NCR) to the pro-herbicide clomazone in populations of E. crus-galli resistant to ALS inhibitors due to increased metabolization. Clomazone dose-response curves, with and without malathion, were performed in imazethapyr-resistant and -susceptible E. crus-galli biotypes. CYPs genes expression and antioxidant enzymes activity were also evaluated. The effective dose to reduce 50% (ED50) of dry shoot weight obtained in the clomazone dose-response curves of the metabolic based imazethapyr-resistant and -susceptible biotypes groups were 22.712 and 58.745 g ha−1, respectively, resulting in a resistance factor (RF) of 0.37, indicating the occurrence of NCR. The application of malathion prior to clomazone increased the resistance factor from 0.60 to 1.05, which indicate the reversion of the NCR. Some CYP genes evaluated were expressed in a higher level, ranging from 2.6–9.1 times according to the biotype and the gene, in the imazethapyr-resistant than in -susceptible biotypes following clomazone application. Antioxidant enzyme activity was not associated with NCR. This study is the first report of NCR directly related to the mechanism of resistance increased metabolization in plants. The occurrence of NCR to clomazone in E. crus-galli can help delay the evolution of herbicide resistance.

Associations between CYP17 gene polymorphisms, temperament and maternal behavior in ewes, and growth in their lambs

This study was conducted to determine temperament and maternal care classes, CYP17 gene polymorphisms, and cortisol status of a group of Norduz ewes. Additionally, the relationships between these factors, their effects on lambs survival and growth characteristics were investigated. A total of 72 ewes were subjected to arena and isolation box tests to determine their temperament classes. The distance the ewe retreated from the lamb during tagging was utilized to assess ewe maternal care classes. Ewes were genotyped for CYP17 628 SNP. Blood samples were collected between lambing and weaning to measure cortisol concentrations of ewes. The survival and growth data for the lambs of these ewes were recorded until weaning. Two temperament (low reactive and high reactive) and 2 maternal care classes (strong and moderate) were present. Two CYP 17 SNP 628 alleles (A and G) and 3 genotypes (AA, AG, and GG) were identified. For the distribution of CYP17 genotype frequencies within the population, the temperament or maternal care classes were not different (P > 0.05). The temperament of ewes did not affect maternal care in our flock. Positive partial correlations between cortisol and total cross, distance to stimulus, and sniffing were determined (P < 0.05). CYP17 genotype was an effective factor for some behavioral traits (i.e., total cross) and cortisol release (P < 0.001). Neither temperament (P = 0.636) nor maternal care classes (P = 0.985) differed with cortisol concentrations. CYP17 genotype, cortisol status, temperament or maternal care class of ewes did not affect birth or weaning weight of their lambs (P > 0.05). Although there was no significant relationship among CYP17 genotype, maternal care, and lamb survival and growth, the effect of CYP17 genotype on some behavioral traits and cortisol release was found to be significant. Further studies with larger animal populations are required to elucidate the possible use of CYP17 SNP 628 genotypes as genetic markers for temperament classification.

Integrated Analysis of miR-430 on Steroidogenesis-Related Gene Expression of Larval Rice Field Eel Monopterus albus.

The present study aims to reveal the mechanism by which miR-430s regulate steroidogenesis in larval rice field eel Monopterus albus. To this end, M. albus embryos were respectively microinjected with miRNA-overexpressing mimics (agomir430a, agomir430b, and agomir430c) or miRNA-knockdown inhibitors (antagomir430a, antagomir430b, and antagomir430c). Transcriptome profiling of the larvae indicated that a total of more than 149 differentially expressed genes (DEGs) were identified among the eight treatments. Specifically, DEGs related to steroidogenesis, the GnRH signaling pathway, the erbB signaling pathway, the Wnt signaling pathway, and other pathways were characterized in the transcriptome. We found that steroidogenesis-related genes (hydroxysteroid 17-beta dehydrogenase 3 (17β-hsdb3), hydroxysteroid 17-beta dehydrogenase 7 (17β-hsdb7), hydroxysteroid 17-beta dehydrogenase 12 (17β-hsdb12), and cytochrome P450 family 19 subfamily a (cyp19a1b)) were significantly downregulated in miR-430 knockdown groups. The differential expressions of miR-430 in three gonads indicated different roles of three miR-430 (a, b, and c) isoforms in regulating steroidogenesis and sex differentiation. Mutation of the miR-430 sites reversed the downregulation of cytochrome P450 family 17 (cyp17), cyp19a1b, and forkhead box L2 (foxl2) reporter activities by miR-430, indicating that miR-430 directly interacted with cyp17, cyp19a1b, and foxl2 genes to inhibit their expressions. Combining these findings, we concluded that miR-430 regulated the steroidogenesis and the biosynthesis of steroid hormones by targeting cyp19a1b in larval M. albus. Our results provide a novel insight into steroidogenesis at the early stage of fish at the molecular level.

Impact of rs2414096 polymorphism of CYP19 gene on susceptibility of polycystic ovary syndrome and hyperandrogenism in Kashmiri women

Polycystic ovary syndrome (PCOS) is the most common reproductive endocrine disorder in pre-menopausal women having complex pathophysiology. Several candidate genes have been shown to have association with PCOS. CYP19 gene encodes a key steroidogenic enzyme involved in conversion of androgens into estrogens. Previous studies have reported contradictory results with regard to association of SNP rs2414096 in CYP19 gene with PCOS and hyperandrogenism in different ethnic populations. Present study was aimed to investigate the impact of SNP rs2414096 polymorphism of CYP19 gene on susceptibility of PCOS and hyperandrogenism in Kashmiri women. Further we also studied the genotypic-phenotypic association for various clinical and biochemical parameters of this polymorphism. Case control study. 394 PCOS cases diagnosed on the basis of Rotterdam criteria and age matched 306 healthy women. We found a significant differences in genotypic frequency (χ2 = 18.91, p < 0.05) as well as allele frequency (OR 0.63, CI 0.51–0.78, χ2 = 17.66, p < 0.05) between PCOS women and controls. The genotype–phenotype correlation analysis showed a significant difference in FG score (p = 0.047) and alopecia (p = 0.045) between the three genotypes. Also, the androgen excess markers like DHEAS (p < 0.001), Androstenedione (p < 0.001), Testosterone (p < 0.001) and FAI (p = 0.005) were significantly elevated in GG genotype and showed a significant difference in additive model in PCOS women. rs2414096 polymorphism of CYP19 gene is associated with the risk of PCOS as well as with clinical and biochemical markers of hyperandrogenism, hence suggesting its role in clinical manifestations of PCOS in Kashmiri women.

Host-pathogen interaction between Asian citrus psyllid and entomopathogenic fungus (Cordyceps fumosorosea) is regulated by modulations in gene expression, enzymatic activity and HLB-bacterial population of the host

The host-pathogen interaction has been explored by several investigations, but the impact of fungal pathogens against insect resistance is still ambiguous. Therefore, we assessed the enzymatic activity and defense-related gene expression of Asian citrus psyllid (ACP) nymphal and adult populations on Huanglongbing-diseased citrus plants under the attack of Cordyceps fumosorosea. Overall, five enzymes viz. superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), glutathione S-transferase (GST), carboxylesterase (CarE), and four genes, namely SOD, 16S, CYP4C68, CYP4BD1, were selected for respective observations from ACP populations. Enzymatic activity of four enzymes (SOD, POD, GST, CarE) was significantly decreased after 5-days post-treatment (dpt) and 3-dpt fungal exposure in fungal treated ACP adult and nymphal populations, respectively, whereas the activity of CAT was boosted substantially post-treatment time schedule. Besides, we recorded drastic fluctuations in the expression of CYP4 genes among fungal treated ACP populations. After 24 hours post-treatment (hpt), expression of both CYP4 genes was boosted in fungal treated populations than controlled populations (adult and nymph). After 3-dpt, however, the expression of CYP4 genes was declined in the given populations. Likewise, fungal attack deteriorated the resistance of adult and nymphal of ACP population, as SOD expression was down-regulated in fungal-treated adult and nymphs after 5-dpt and 3-dpt exposure, respectively. Moreover, bacterial expression via the 16S gene was significantly increased in fungal-treated adult and nymphal ACP populations with increasing post-treatment time. Overall, our data illustrate that the fungal application disrupted the insect defense system. The expression of these genes and enzymes suppress the immune function of adult and nymphal ACP populations. As it is reported first time that the applications of C. fumosorosea against ACP reduce insect resistance by interfering with the CYP4 and SOD system. Therefore, we propose new strategies to discover the role of certain toxic compounds from fungus, which can reduce insect resistance, focusing on resistance-related genes and enzymes.

Ameliorative Effects of Aspergillus awamori against the Initiation of Hepatocarcinogenesis Induced by Diethylnitrosamine in a Rat Model: Regulation of Cyp19 and p53 Gene Expression.

Hepatocellular carcinoma (HCC) is the most common cancer in humans. Despite advances in its treatment, liver cancer remains one of the most difficult cancers to treat. This study aimed to investigate the ameliorative action and potential mechanism of Aspergillus awamori (ASP) administration against the initiation process of liver carcinogenesis induced by diethylnitrosamine (DEN) in male Wistar rats. Seventy-two male rats were divided equally into eight groups as follows, Group 1: untreated control; Group 2: DEN (200 mg/kg bw) intra-peritoneally for the initiation of HCC; Groups 3–5: DEN + ASP at a dose of 1, 0.5, and 0.25 mg/kg bw and groups 6–8: ASP at a dose of 1, 0.5, and 0.25 mg/kg bw. Supplementation of A. awamori significantly lightened the adverse impacts induced by DEN via restoring the leukogram to normal, lowering the elevated serum aspartate aminotransferase (AST), alanine transaminase (ALT), and γ-glutamyl transferase (GGT), and alkaline phosphatase (ALP). Furthermore, it enhanced the hepatic antioxidant capacity through increasing the reduced glutathione (GSH) level and catalase (CAT) activity with a marked reduction in malondialdehyde (MDA) level. In addition, it decreased the positive GST-P foci. Likewise, a significant alteration of DEN-associated hepatocarcinogenesis occurred through inhibiting cytochrome P450 (Cyp19) and activating p53 gene expression. In conclusion, supplementation of A. awamori counteracts the negative effects of DEN, inhibits the early development of GST-P-positive foci and could be used as a new alternative strategy for its chemo-preventive effect in liver cancer. To the best of our knowledge, the present study is the first to report the hepato-protective effect of A. awamori in induced hepatocarcinogenesis.

Aromatase and the three little paralogs.

The rapid progress of scientific knowledge is continuously built on established earlier findings. Integrating previous observations with more recent data can be challenging and occasionally well-established data is unfortunately overlooked. This may lead to unnecessary redundancy in research and, in the worst-case scenario, to misinterpretation of data. In the present contribution we would like to draw attention to such a circumstance, which has crept into several recent papers on expression and functional relevance of the porcine CYP19 gene cluster that encodes functionally distinct isoforms of aromatase cytochrome P450 (aromatase) in pigs.

Independent and Interactive Effect of CYPs and GSTs Genetic Variants and Tobacco Smoking on the Risk of Non-Small Cell Lung Carcinoma

CYP and GST gene families detoxify tobacco carcinogens and have been linked to the risk of non-small cell lung carcinoma (NSCLC). Independent and combined effects of CYP and GST genetic variations and smoking on the risk of non-small cell lung carcinoma (NSCLC) and its sub-histological types. We modelled an epistatic interaction via the effects of particular genotypes in two genes as OR (odds ratio), OR1, and OR2, a combination of both genotypes were characterized as ORcombine. In contrast, the two ORs' epistatic interaction for the individual genotypes has been represented as ORinteraction = ORcombine/(OR1 × OR2). The variant genotypes of CYP2A6 (OR:4.2, p <0.001), GSTT1 (OR:3.9, p <0.001), and GSTM1 (OR: 4.5, p <0.001) were showed a significant risk with NSCLC. GSTM1 (del.)/CYP2A6 (variant) genotype was associated with a higher risk of NSCLC (OR:12.5, p <0.001). GSTM1 (del.)/CYP2A6 (Ser/Pro+Pro/Pro) and GSTM1 (del.)/CYP2A13 (CT+TT) interacted redundantly (ORintraction = 0.66 and 0.64). A co-suppressive interaction was observed between GSTT1 (del.)/CYP2A6 (Ser/Pro+Pro/Pro) (ORintraction = 0.41). Simultaneously, both GSTT1/GSTM1 del. genotype was associated with a significantly higher risk to NSCLC. In contrast, GSTT1 del./GSTM1 del. genotype interaction displayed a co-suppressive effect (ORintraction = 0.15). CYP1A1(TC+CC)/CYP2A13(CT+TT)mutually interacted synergistically (ORintraction = 1.27).CYP1A1 (TC+CC)/GSTP1 (Val/Val+Ile/Val) genotype demonstrated an additive (ORintraction = 1) effect. GSTP1(Val/Val+Ile/Val) interacts with GSTT1 (del.) genotype exerted a suppressive effect (ORintraction = 0.69). CYP2A6 in smokers increased risk by 4.2 (p = 0.001) to 5.6 fold (p <0.001), while GSTM1 and GSTT1 were independent of smoking. Epistatic interactions revealed that CYPs/GSTs might follow a web of the interactions to modify the risk of NSCLC.

Effects of Short and Long-Term Soy Protein Isolate Intake on Hepatic Cytochrome P450 Expression in Obese Zucker Rats

ObjectivesTo determine the effects feeding for 8 (short-term) and 16 weeks (long-term) soy protein isolate on hepatic CYP gene expression. Methods7-weeks old rats were randomly assigned to either a casein (CAS) or a soy protein isolate (SPI) diet. They were provided the diets ad libitum for 8 and 16 weeks. Rats were euthanized and livers were stored at – 80°C. RNA was extracted from liver samples, and sequenced to obtain transcriptomic data (RNAseq). Ingenuity Pathway Analysis software (IPA, Qiagen, CA) was used in the analysis of global gene expression data. This analysis includes predictions of activation or inhibition of molecules or upstream regulators and functions based on a generated z-score and p-value of overlap (P = 0.05). Z-scores were consider significant when > 2 (activation) and < –2 (inhibition). ResultsComparing short- vs long-term feeding revealed an increase in the number of down-regulated CYP genes from only 3 at 8 weeks of SPI diet to 10 at 16 weeks of same diet (P < 0.05). In contrast, upregulated CYP gene numbers showed a small increase in long-term SPI diet compared to short-term, from 14 genes at 8 weeks to 17 genes at 16 weeks (P < 0.05). In addition, we present a predicted activation of the transcription factor Aryl hydrocarbon receptor (AHR, activation z-score = 2.146, P = 4.20E-11), linked to the subsequent activation or up-regulation of various CYPs genes, indirectly leading to the activation and inhibition of two main metabolic functions under SPI feeding: conversion of lipid (lipid metabolism) –predicted to be activated (z-score = 2.089, P = 2.77E-08), and recruitment of phagocytes (inflammatory response) –predicted to be inhibited (z-score = –2.311, P = 2.10E-05). ConclusionsThrough global gene expression analysis we showed that gene expression of drug-metabolizing cytochrome P450 genes was modified in genetically obese Zucker rats after being fed a soy-based diet for short- and long-term, and that this change could have an important role in attenuation of liver steatosis. Further research is needed to corroborate these results. Funding SourcesThis study was supported in part by the College of Medicine’s University Medical Group (RH) and the Arkansas Biosciences Institute (WB, RH).

The effects of chitosan nanoparticles on genes expression of artemisinin synthase in suspension culture of Artemisia annua L: A comparative study

Background: Despite significant efforts, the artemisinin-based drugs are still very expensive due to the limited production of this metabolite within wild Artemisia spp . plants. Therefore, the current work set out to evaluate the effect of chitosan nanoparticles, as a novel elicitor to characterize the expression of genes functioning in artemisinin synthesis pathway using a comparative experimental investigation. Methods: The suspensioncultures of A. anuua were exposed to 5, 10, 15 mg/L of chitosan nanoparticles (during 8, 24, 48 and 72 h upon treatment). The expression of DBR2, SQS, CYp , ADS, CPR and ALDH genes were quantified by qRT-PCR technique. Results: Chitosan nanoparticles were effective in inducing artemisinin production at 15 mg/L after 8 h, and 5 and 10 mg/L after 72 h of elicitation, in which all the ADS, CYp , CPR, DBR2 and ALDH genes were upregulated except SQS. Conclusion: The treatment of 5 mg/L after 72 h, when cells entered the stationary and then death phases, is recommended because it seems chitosan nanoparticles require more time to up-regulate the ADS, CYP and ALDH genes and thereby probably enhance the artemisinin content. The results suggest that chitosan nanoparticles can be used as a novel effective elicitor for artemisinin production.

Importance of Cytochrome P450 gene family from metabolite biosynthesis to stress tolerance: A review

CYP450 short for Cytochrome P450 is an enzyme superfamily involved in catalysing numerous biochemical reactions. It is known for its involvement in diverse plant processes. CYP450 is widely distributed in the case of eukaryotes and is said to exist in all domains of living organisms including bacteria, plants as well as mammals. The enzyme of this family plays a key role in the oxidative transformation of both endogenous as well as exogenous molecules. The growth and development of the plants are affected by several biotic and abiotic stresses regularly. They downgrade the crop quality and lead to a sharp decline in the productivity of the crop. CYP plays important role in providing protection to plants against these stresses. It does that by taking an active part in various detoxification as well as biosynthetic pathways. The objective of this review is to explore the role of CYP 450 in various metabolite biosynthesis as well as tolerance to various biotic and abiotic stresses in plants. This review aims to provide a framework for further investigation of the CYP450 gene family in plants and will also provide a strong base for the characterization of their diverse role in defence mechanisms against different abiotic and biotic stress and metabolite biosynthesis.

Therapy response prediction in major depressive disorder: current and novel genomic markers influencing pharmacokinetics and pharmacodynamics.

Major depressive disorderis connected withhigh rates of functional disability and mortality. About athird of the patients are at risk of therapy failure. Several pharmacogenetic markersespecially located in CYP450 genes such as CYP2D6 or CYP2C19 are of relevance for therapy outcome prediction in major depressive disorder but a further optimization of predictive tools is warranted. The article summarizes the current knowledge on pharmacogenetic variants, therapy effects and side effects of important antidepressive therapeutics, and sheds light on new methodological approaches for therapy response estimation based on genetic markers with relevance for pharmacokinetics, pharmacodynamics and disease pathology identified in genome-wide association studyanalyses, highlighting polygenic risk score analysis as a tool for further optimization of individualized therapy outcome prediction.