Cytochrome P450 oxidoreductase deficiency in an infant / 中华围产医学杂志

This study reported the diagnosis and treatment of cytochrome P450 oxidoreductase deficiency (PORD) in a male infant. The patient was admitted to Children's Hospital Affiliated to Shandong University at the age of 38 days due to nasal obstruction and feeding difficulties presented at 10 d after birth, as well as less weight gain. Physical examination showed craniosynostoses, hand and foot deformities, and normal external genitalia. Laboratory examination revealed mildly elevated serum adrenocorticotrophic hormone and decreased level of baseline cortisol. A homozygous mutation of c.1370G>A(p.R457H) in POR gene was detected by whole-exome sequencing, which confirmed the diagnosis of PORD. Skeletal deformities complicated by external genital malformations and/or adrenocortical hormone abnormalities are important diagnostic indicators for PORD.

Role of the cytochrome P450 family in metabolic-associated liver diseases / 临床肝胆病杂志

The cytochrome P450 (CYP) family is the most important drug-metabolizing enzyme in human body and is responsible for the metabolism of endogenous and exogenous compounds. As the main site of the expression of the CYP family, the liver is the metabolic center of drugs, and in recent years, the role of the CYP family in the liver has attracted wide attention from the scholars in China and globally. This article reviews the distribution differences of the CYP family from the aspects of anatomy, genetics, and genomics, changes in the expression of the CYP family in the pathological processes such as non-alcoholic fatty liver disease, alcoholic liver disease, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma, and the effect of CYP family-mediated enzyme activity on the treatment effect of pharmacotherapy for metabolic-associated liver diseases, in order to provide important enlightenment for identifying key drug intervention targets in diseases and enhancing clinical efficacy and safety.

Analysis and clinical significance of cytochrome P 450 2C19 gene in patients with cardiovascular and cerebrovascular diseases in southern Yunnan / 中国基层医药

Objective:To analyze the distribution and clinical significance of cytochrome P 450 2C19 (CYP2C19) gene in patients with cardiovascular and cerebrovascular diseases in southern Yunnan. Methods:The data of 245 patients with cardiovascular and cerebrovascular diseases who received treatment in Southern Central Hospital of Yunnan Province between May 2019 and June 2020 were retrospectively analyzed. The distribution of CYP2C19 gene and its relationship with nationality, age, sex, blood lipids, hypertension, and diabetes were analyzed and compared between southern Yunnan and other regions.Results:The proportions of seven phenotypes of CYP2C19 gene *1/*17, *1/*1, *1/*2, *1/*3, *2/*2, *2/*3, *3/*3 in 245 patients were 2.86%, 38.37%, 39.18%, 5.31%, 9.39%, 4.08% and 0.82%, respectively. The proportions of individuals with superfast/ultrafast metabolism, fast metabolism, intermediate metabolism, and slow metabolism in 245 patients were 2.86%, 38.37%, 44.49%, and 14.29%, respectively. The frequency of polymorphisms in the CYP2C19 gene was consistent with the Hardy-Weinberg equilibrium ( P > 0.05), which was constant and representative. The Fisher test showed that the CYP2C19 gene distribution of patients with cardiovascular and cerebrovascular diseases in southern Yunnan was not greatly correlated with nationality, age, sex, underlying disease, blood lipids, and the types of cardiovascular and cerebrovascular diseases (all P > 0.05). There was a significant difference in CYP2C19 gene distribution in patients from southern Yunnan versus Dongguan, Jiangxi, Fujian, northern Sichuan, Chifeng, Xiamen, Shaanxi, and Kunming ( P < 0.001, < 0.001, 0.045, 0.008, 0.001, 0.005, < 0.001, 0.016). Conclusion:The distribution of CYP2C19 gene in patients with cardiovascular and cerebrovascular diseases in southern Yunnan is not obviously correlated with nationality, age, sex, underlying diseases, blood lipids, and the types of cardiovascular and cerebrovascular diseases. CYP2C19 gene distribution is related to regional distribution, which can guide personalized medication in different regions.

Immunopharmacology 2020. V International Congress on Immunopharmacology

The Organizing Committee of the V International Congress on Immunopharmacology (Immunopharmacology 2020) organized by the Cuban Society of Pharmacology, BioCubaFarma and the International Union of Basic and Clinical Pharmacology (IUPHAR) would like to invite you to participate in this important event, scheduled for June 9 to 13, 2020 at the Convention Centre of the Melia Marina Varadero Hotel, Varadero Beach, Matanzas, Cuba. The Congress will be formed by different workshops and symposia such as: Fifth workshop on new advances in immunopharmacology Fifth workshop on neuroimmunology, neuroimmunopharmacology and neuroimmunomodulation. Immunopharmacology of brain tumors Symposium on hereditary ataxias Fifth symposium on pharmacology of cytochrome P450 and transporters Fourth symposium on inflammation and pain 2nd symposium on NFkB Synthetic peptides as immunopharmacological tools Novel designs in clinical trials. Biosimilar pharmaceuticals Pharmacogenetics, pharmacogenomics, proteomics and phosphoproteomics Immune response in cancer First symposium on business and international cooperation on biologics Immunopharmacology 2020 is sponsored by: Cuban Society of Pharmacology (SCF) International Union of Basic and Clinical Pharmacology (IUPHAR) Latin-American Association of Pharmacology (ALF) PAHO / WHO BioCubaFarma National research centers: Finlay Vaccine Institute (IFV); Center of Genetic Engineering and Biotechnology (CIGB); Center of Molecular Immunology (CIM); Center for Control of Drugs, Equipment and Medical Devices (CECMED); National Center for Animal and Plant Health (CENSA); Tropical Medicine Institute "Pedro Kourí" (IPK); National Center for Biopreparations (BioCEN); Center for Drug Research and Development (CIDEM); Center for Clinical Trials (CENCEC); among others International Manufacturers and Companies The key objectives of the Congress are: To provide a progressive state-of-the-art report for scientists, manufacturers, governmental authorities and healthcare workers, who need to be updated about the latest scientific developments for human vaccines, including basic science, product development, market introduction, immunization programs and epidemiological surveillance. To promote the scientific collaboration among experts and institutions through the experience exchange, the presentation of results and the discussion on the conference topics. To accelerate progress in the development of vaccines and the acceptance and introduction of new methods and technologies. Opening lectures, oral presentations and posters will provide you the opportunity to be involved in a high quality congress to discuss about the progress in the field of immunology and pharmacology sciences(AU)

Expression and clinical significance of aryl hydrocarbon receptor in peripheral blood and skin lesions of patients with atopic dermatitis / 中华皮肤科杂志

Objective To detect levels of aryl hydrocarbon receptor (AhR) and its downstream molecules in peripheral blood mononuclear cells (PBMCs) and sera from patients with atopic dermatitis (AD),and to analyze the correlation of their expression with serum cytokines and the severity of AD.Methods Real-time quantitative PCR (RT-PCR) was performed to analyze mRNA expression of AhR,cytochrome P4501A (CYP1A1),AhR repressor (AHRR),AhR nuclear translocator (ARNT) in PBMCs from 29 AD patients and 17 healthy controls,enzyme-linked immunosorbent assay (ELISA) to detect serum levels of interleukin (IL)-1β,IL-6,tumor necrosis factor (TNF)-α,IL-4,IL-22 and AhR in the AD patients,and immunohistochemical study to determine AhR expression in skin lesions of the AD patients and normal skin tissues of 21 patients with pigmented nevus.Measurement data were compared by using unpaired Student's t test,enumeration data were compared by using chi-square test,and correlations between indices were analyzed by using Pearson correlation analysis.Results The serum level of AhR was significantly higher in the AD group (41.26 ± 4.52 pmol/L) than in the healthy control group (33.73 ± 2.49 pmol/L,t =6.507,P ＜ 0.001).Compared with the healthy control group,the AD group showed significantly increased mRNA expression ofAhR (1.572 ± 0.392 vs.1.000 ± 0.173,t =6.819,P =0.007),AHRR (2.402 ±1.716 vs.1.000 ± 0.788,t =3.722,P =0.039),CYP1A1 (2.258 ± 1.598 vs.1.000 ± 0.796,t =3.400,P =0.002) and ARNT (1.383 ± 0.842 vs.1.000 ± 0.586,t =1.653,P =0.105) in PBMCs.The AhR expression in skin lesions in the AD group was significantly higher than that in normal skin tissues in the control group (0.191 ± 0.041 vs.0.087 ± 0.017,t =10.036,P ＜ 0.001).In the AD group,the mRNA expression of AhR in PBMCs was positively correlated with eczema area and severity index score (r =0.448,P =0.019) and the serum IL-6 level (r =0.377,P =0.046),and the AHRR mRNA expression was positively correlated with the serum IL-1β level (r =0.467,P =0.021).Conclusion AhR and its downstream molecules were highly expressed in the AD patients compared with healthy controls,and the AhR expression was positively correlated with the serum IL-6 level and AD severity in AD patients,suggesting that the AhR signaling pathway may play a certain role in pathogenesis of AD and AhR may serve as an efficient index for evaluating AD severitv.

In Silico Identification of Novel Tuberculosis Drug Targets in Mycobacterium tuberculosis P450 Enzymes by Interaction Study with Azole Drugs

@#Introduction: Tuberculosis (TB) is one of the utmost serious infectious diseases worldwide. The emergence of multidrug resistance demands the development of better or new putative drug targets for tuberculosis. Recent studies suggest Mycobacterium tuberculosis cytochrome P450 enzymes as promising drug targets and azole drugs as potential inhibitors. Methods: Various computational tools, like Expasy Protparam, Swiss model, RaptorX and Phyre2 were used to analyze 12 Mycobacterium tuberculosis P450 enzymes and determine their three-dimensional structure. The structural validation was done through a Ramachandran plot using RAMPAGE server. The docking of P450 enzymes with azole drugs was done with autodock ver 4.2.6. Results: Based on sub-cellular localization prediction using CELLO tool, P450 enzymes CYP123A1, CYP132A1, CYP135A1, CYP136A1, CYP140A1, and CYP143A1 were predicted to be in the cytoplasm. Through structure assessment by Ramachandran plot, the best homology modelled proteins were docked with azole drugs like clotrimazole, croconazole, econazole, fluconazole, itraconazole, itraconazole, ketaconazole and micronazole by using autodock. By docking method it is identified that ketaconazole drug has a high affinity towards most of the mycobacterium P450 enzymes followed by the itrconazole drug. CYP123A1 enzyme is preferable as a drug target due to high binding affinity towards ketoconazole followed by CYP135A1, CYP140A1 enzymes. Conclusion: This study would help in identifying putative novel drug targets in Mycobacterium tuberculosis, which can lead to promising candidates for the optimization and development of novel anti-mycobacterial agents.

Association between cytochrome P450 gene polymorphism and drug-induced liver injury / 临床肝胆病杂志

As the prevalence rate of drug-induced liver injury increases year by year, the pathogenesis of drug-induced liver injury has become the focus of attention. As a large family, CYP450 enzymes participate in almost all oxidative metabolic reactions of drugs in the human liver. Recent studies have shown that CYP450 enzyme gene polymorphisms lead to the differences in pharmacodynamics between individuals, and therefore, exploring the role of CYP450 enzyme gene polymorphisms in drug-induced liver injury may promote the understanding of the pathogenesis of drug-induced liver injury. This article reviews the CYP450 enzyme polymorphisms that have been found to be associated with drug-induced liver injury.

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase gene mutation: a case report / 中华围产医学杂志

We hereby reported the clinical manifestations and genetic diagnosis of a rare case of congenital adrenal hyperplasia (CAH) caused by cytochrome P450 oxidoreductase ( POR ) gene mutation. The case was an 11-year-old girl presented with craniofacial and skeletal malformation such as a depressed nasal bridge, radiohumeral synostosis and camptodactyly in feet. Moreover, she was diagnosed with ambiguous genitalia, and her mother had obvious masculine features during pregnancy. Laboratory tests showed that the levels of peripheral blood progesterone, 17-hydroxyprogesterone and adrenocorticotrophic hormone (ACTH) had increased significantly, which were consistent with the symptom of CAH. Genetic testing revealed a complex heterozygous mutation in POR gene of maternally inherited c.744C>G (p.Tyr248Ter) and paternal inherited c.1370G>A (p.Arg457His). Therefore, she was diagnosed with cytochrome P450 oxidoreductase deficiency (PORD), which is a rare type of CAH. The patient received oral glucocorticoid therapy and underwent knee arthroplasty.

Association study between a genetic polymorphism in cytochrome P450 19 gene rs10046 and colon and rectal cancer / 中国医师杂志

Objective To investigate the relationship between the polymorphism of cytochrome P450 19 (CYP19) gene rs10046 and the risk of colon and rectal cancer.Methods Using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to analyze gene polymorphism in CYP 19 gene rs10046 in 198 cases of colon and rectal cancer patients (case group) and 309 cases of healthy controls (control group).The genotype frequency and relative risk of CYP19 gene rs10046 between the two groups were compared and the relationship with the clinicopathological features of colorectal cancer was analyzed.Results In case group,the prevalence rates of CYP19 rs10046 genotypes C/C,C/T and T/T were 28.3％,44.4％ and 27.3％,respectively,and 17.2％,51.8％ and 31.1％ in the control group,respectively,with statistical significant difference (P ＜ 0.05).Compared with wild-type C/C,the susceptibility of colorectal cancer with the genotypes of C/T and T/T was decreased by 0.521 (95％ CI:0.330-0.822)and 0.532 (95 ％ CI:0.322-0.880) respectively.Moveover,in the non-smoking group,the risk of colorectal cancer with genotype T/T or C/T was decreased by 0.409 (95％ CI:0.210-0.798) compared with genotype C/C.The interaction was not exist in smoking group.Conclusions The polymorphism of CYP19 gene rs10046 is related to the susceptibility of colon and rectal cancer.The T/T,C/T genotype of CYP19 rs10046 decrease the risk of colon and rectal cancer,and which might be the protective factor of colon and rectal cancer.

Correlation between cytochrome P450 2C19 gene polymorphism and cardiovascular event after PCI in coronary heart disease / 重庆医学

Objective To investigate the correlation between cytochrome P450(CYP) 2C19 gene polymorphism with major adverse cardiovascular events(MACE) after PCI in the patients with coronary heart disease(CHD).Methods A total of 233 patients with CHD undergoing PCI in the cardiology department of our hospital from January 2014 to January 2015 were selected.All patients were given the standardized dual anti-platelet therapy of aspirin and clopidogrel.The occurrence situation of MACE within 1 year(unstable angina pectoris,cardiac death,in-stent restenosis,non-fatal myocardial infarction) was obtained by follow up.All patients were divided into the MACE group and non-MACE group.The PCR solubility curve was adopted to detect the CYP2C19 gene polymorphism.Results Among 233 cases of CHD,37 cases (15.88％) developed cardiovascular events and 196 cases (84.12 ％) did not develop vascular events;the age,sex,hypertension and diabetes mellitus had no statistical differences between the two groups(P＞0.05).The frequency of CYP2C19 * 1 in the included cases was 68.45％,which of CYP2C19 * 2 was 28.33％ and which of CYP2C19 * 3 was 3.22％.The extensive-metabolism,intermediate metabolism and slow metabolism types in the cardiovascular events group accounted for 5.41 ％,64.86 ％ and 29.73 ％ respectively,while which in the non event group were 59.69 ％,29.08％ and 11.22％ respectively,the CYP2C19 genotype distribution had statistically significant difference between the two groups(P＜0.05).The multivariate Logistic regression analysis showed that CYP2C19 intermediate metabolism type [OR 2.562,95％CI(2.825,7.350),P=0.021 0],slow metabolism type [OR 5.139,95％CI(1.289,5.232),P＜0.01],hypertension [OR 2.480,95 ％CI(1.079,5.698),P=0.032 4],smoking[OR 4.802,95％CI(1.082,18.371),P=0.029 0] were the independent risk factors for the occurrence of cardiovascular events in the patients with CHD.Conclusion CYP2C19 * 2 and CYP2C19 * 3 gene polymorphism are the independent risk factors for MACE occurrence after PCI in the patients with CHD.

Effect of CYP2C9 gene polymorphism on warfarin dosage / 中华老年心脑血管病杂志

Objective To study the association between CYP2C9 gene polymorphism and warfarin maintenance dosage in anticoagulation therapy.Methods 200 Han patients admitted to our hospital for heart valve replacement were included in this study.CYP2C9 * 2,CYP2C9 * 3,CYP2C9 *c65 in CYP2C9 gene were sequenced using the CAPS technique and conventional DNA sequencing method.Dosages of warfarin used in patients carrying different genes were analyzed.Results No mutation of CYP2C9 * 2 but only one kind of allele C was detected in 200 patients.The genotype of CYP2C9 * 2 was C/C wild type.Allelic gene was detected at CYP2C9 * 3 A and C,with A/A wild type detected in 171 patients,A/C heterozygote mutation type detected in 18 patients,and C/C heterozygote mutation type detected in 11 patients respectively.The frequency of allelic genes A and B was 94.3 ％ and 5.7 ％ respectively.A significant difference was found between CYP2C9 * 3 mutation and warfarin dosage (P＜0.05).The dosage of warfarin reduced 18.46％ and 76.0％ respectively in patients carrying A/C heterozygote mutation type and in those carrying C/C heterozygote mutation type.Two kinds of allelic gene were detected at CYP2C9 * c65 G and C,with G/G wild type detected in 182 patients and G/C heterozygote mutation type detected in 18 patients respectively.No significant association was found in warfarin maintenance dosage for patients carrying G/G wild type and G/C heterozygote mutation type.Conclusion CYP2C9 gene polymorphism is associated with warfarin maintenance dosage in anticoagulation therapy.

Correlation between prostacyclin synthase gene rs5602 polymorphism and ischemia stroke in Chinese Han population / 国际脑血管病杂志

Objective To investigate the correlation between prostacyclin synthase (prostaglandin I2 synthase, PGIS) gene rs5602 single nucleotide polymorphism and ischemia stroke in Chinese Han population. Methods The patients with ischemia stroke and healthy controls in Chinese Han population were enroled. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF MS) was used to detect the rs5602 polymorphism. Results A total of 297 patients with ischemic stroke (male 177 and female 120) and 291 healthy controls (male 165, female 126) over the same period were enroled. The frequencies of TT genotype (31. 1% vs. 43. 6% ; χ2 = 5. 773, P = 0. 016) and T alele (56. 8% vs. 65. 8% ; χ2 = 5. 793, P = 0. 016) in the male patients with ischemic stroke were significantly lower than those in the male healthy controls. Multivariate logistic regression analysis showed that the rs5602 TT genotype was a protective factor for ischemic stroke in male (odds ratio 0. 260, 95% confidence interval 0. 118-0. 570; P = 0. 001). Conclusions PGIS gene rs5602 polymorphism is associated with ischemic stroke in male in Chinese Han population.

Arachidonic acid metabolic pathway-related genes interactions increase the incidences of stroke and vulnerable plaques / 中华神经科杂志

Objective To investigate whether metabolic pathway-related gene polymorphisms are associated with arterial plaque stability and their gene-gene interactions increase the risk of cerebral infarctions.Methods Totally 294 patients with atherothrombosis stroke admitted to the Department of Neurology, the Third Affiliated Hospital of Wenzhou Medical University from September 2010 to December 2012 were divided into a carotid vulnerable plaque group ( n=69 ) and a stable plaque group ( n=225 ) according to the results of carotid B-mode ultrasonography.A total of 282 healthy volunteers excluded carotid plaque and stroke were enrolled as well.Genetic polymorphisms of ALOX5AP and CYP3A5, CYP2C9*2, CYP2C9*3 and EPHX2 were genotyped using polymerase chain reaction and mass spectrometry analysis.The SPSS16.0 software was used to compare genotype frequencies and the generalized multifactor dimensionality reduction ( GMDR ) method was applied for gene-gene interaction analyses.Results The results showed that EPHX2 GG genotype might protect against stroke ( OR =0.520, 95% CI 0.288 -0.940, P=0.030).The distribution of CYP3A5 genotypes showed statistically significant differences (χ2 =7.284, P=0.026) between the vulnerable plaque ( AA: 5 cases, AG: 36 cases, GG: 28 cases) and stable plaque ( AA: 26 cases, AG: 77 cases, GG: 122 cases ) groups.Multivariate Logistic regression analysis showed that the GG genotype of CYP3A5 was protective factor for unstable plaques ( OR=0.405, 95%CI 0.178 -0.920, P =0.031 ).Differences in other SNPs did not reach statistical significance between the two groups.The GMDR analysis showed a significant gene-gene interaction between SG13S114 and A6986G, with scores of 10 for cross-validation consistency and 9 for the sign test (P=0.011).The best model for ischemic stroke was found to be SG13S114 AA and A6986G AA.Adjusting for age, hypertension and diabetes, the certain gene-gene interaction predicted a significantly higher risk of cerebral infarction (OR=1.804, 95%CI 1.180-2.759, P=0.006).Conclusions The EPHX2 G860A gene might be linked with the incidence of cerebral infarctions.Only a CYP3A5 gene polymorphism might be associated with carotid plaque instability in patients with stroke.The gene-gene interaction predicts a significantly higher risk of cerebral infarction.There is a 1.804-fold increased risk for ischemic stroke in individuals with these combined genetic factors.

Computerized optimization of high-performance liquid chromatographic method by using DryLab to test and isolate six cytochrome P450 probe substrates / 国际中医中药杂志

Objective DryLab software was used to assist high performance liquid chromatography (HPLC) method to test and isolate six Cytochrome P450 (CYP450) probe substrates.Methods Six CYP450 probe substrates were selected and the right HPLC method was developed and validated with the assistance of DryLab software.Results The new HPLC method with the assistance of DryLab software could test and isolate six probe substrates with degrees of isolation more than 2.00. The correlation coefficients (R> 0.999 8) indicated high linear correlation between the concentrations and the peak areas among six probe substrates. Recovery studies showed good results for all the probe substrat from 86.38% to 110.29%. And therelative standard deviation (RSD) ranged from 1.69% to 3.80% with its intra-day and inter-day precision ranging from 0.42% to 2.01%, and 1.36% to 2.29%, respectively.Conclusions The developed HPLC method with the assistance of DryLab could test and isolate six probe substrates with shortertime than the HPLC method alone.

DNA methylation of oxidative metabolic enzymes:research progres / 中国药理学与毒理学杂志

DNA methylation is part of the epigenetic modification process,which can lead to aberrant gene expression. Cytochrome P450 enzyme,cyclooxygenase,lipoxygenase and monoamine oxidase are a class of enzymes produced by human tissues,which are involved in the oxidization pro?cess of endogenous and exogenous chemicals. The methylation patterns of these enzyme genes are dif?ferent between normal tissues and pathological ones. Abnormal methylation patterns will change en?zymes′expression and function,and affect the occurrence and development of diseases. This paper re?viewed the characteristic changes of four oxidative metabolic enzyme genes in certain diseased tis?sues,the impact on methylation status of the metabolic activity of chemicals and on human health. It is hoped that this review can provide a new theoretical basis for the study on the toxic mechanism of chemicals and for diagnosis of diseases.

Efecto de los medicamentos antiepilépticos en el metabolismo de la vitamina D y el impacto negativo relacionado al déficit / Effect of antiepileptic drugs in the metabolism of vitamin D and negative impact related to the deficit

Resumen: la alteración en el metabolismo de la vitamina D ha ido creciendo en importancia hasta considerarse un problema de salud pública. Cada vez son más frecuentes las etiologías relacionadas al déficit de la vitamina D y con consecuencias a largo plazo, lo que hace necesario conocer no sólo las bases moleculares del metabolismo de la vitamina D, con especial atención en la participación de las enzimas de la familia del citocromo P450, sino la descripción de las vías metabólicas, la interacción con el receptor específico, las acciones genómicas y no genómicas, sus resultados en el metabolismo óseo y las acciones extra esqueléticas. Además, la acción directa de los antiepilépticos sobre las enzimas de la citocromo P450 y su efecto negativo sobre los niveles de la vitamina D y el metabolismo óseo. Esta revisión pretende brindar las bases que permitan extrapolar estos conceptos a la práctica clínica e identificar los pacientes con riesgo de hipovitaminosis D debido al uso crónico de antiepilépticos que requieren una conducta terapéutica. Es necesario tener presente que en la actualidad no hay un protocolo clínico universal sobre el seguimiento de estos pacientes incluso con la mejoría en el acceso a recursos diagnósticos.

Abstract: alteration in vitamin D metabolism has been growing in importance until be considered a heart public problem. Increasingly are more frequent the etiologies related to vitamin D deficiency and the long-term effects, which making necessary to know not only the molecular basic of vitamin D metabolism, with special attention to the parcipation of cytochrome p450 family enzymes, but also the descrition of the metabolic pathways, interaction with the specific receptor, genomic and non-genomic actions, result in bone metabolism and extraskeletal actions. In addition, the direct action of antiepileptic drugs on cytochrome p450 enzimes and their negative effects on vitamin D levels and bone metabolism. this review aims provide the basic that allow to extrapolate these concepts to clinical practice and identify patients at risk of vitamin D deficiency due to the chronically use antiepileptic drugs thal requisre therapeutic conduct. It should be remembered that currently there is no universal protocol on clinical monitoring of these patients even with the improvement in acess to diagnostic resources.

Relationship between cytochrome P450 2C19 gene polymorphism and antiplatelet effect of clopidogre in patients with ischemic stroke / 中国脑血管病杂志

Objective To investigate the relationship between cytochrome P 450 (CYP)2C19*2 / *3 gene polymorphism and antiplatelet effect of clopidogre in patients with ischemic stroke. Methods A total of 102 consecutive patients with acute ischemic stroke admitted to the Suzhou Integrated Traditional and Western Medicine Hospital from November 2012 to February 2014 were enrolled. The patients allergic to clopidogre,intolerant to clopidogrel,and recently using clopidogre were excluded. The patients were divided into a strong metabolic type group (n = 39),a moderate metabolic type group (n = 54),and a week metabolic type group (n = 9)according to the conditions of CYP2C19*2 and *3 locus mutation. The genotypes of the CYP2C19*2 and *3 were detected by the direct gene sequencing method in all patients. The maximum aggregation ratio (MAR)of platelet and platelet reactivity index (PRI)were detected beforeand 7 d after taking clopidogre 75 mg. Results (1)According to the CYP2C19*2 and CYP2C19*3, the genotyping was performed. The strong metabolic type group included *1 / *1 type 39 cases (38. 2%);the moderate metabolic type group included *l / *2 type 44 cases (43. 1%);*l / *3 54 cases, 10 (9. 8%);and the week metabolic type group included *2 / * type 27 cases (6. 9%);*2 / *3 type 2 cases (2. 0%). No *3 / *3 type was detected. (2)There were no significant differences in MAR before taking clopidogrel among the 3 groups (all P > 0. 05). After taking clopidogrel for 7 days,MAR and PRI were detected from strong to weak,followed by the week metabolic type group (49 ± 12% vs. 64 ± 15%), the moderate metabolic type group (42 ± 13% vs. 56 ± 14%),and the strong metabolic type group (33 ± 10% vs. 43 ± 12%);MAR was detected from high to low,followed by the strong metabolic type group (20 ± 12%),the moderate metabolic type group (10 ± 8%),and the week metabolic type group (7 ± 3%). Comparing the moderate metabolic type group and the week metabolic type group with the strong metabolic type group,there were significant differences between MAR,the decreased MAR and PRI (all P 0. 05). Conclusion The CYP2C19*2 and *3 gene polymorphisms may affect MAR and PRI after taking clopidogrel in patients with ischemic stroke.

Enzyme kinetics of psoralen and isopsoralen in rat and human liver microsomes / 中国药理学与毒理学杂志

OBJECTIVE To investigate and compare the enzyme kinetic characters of psoralen (PRN)and isopsoralen(IPRN)in rat and human liver microsomes. METHODS PRN and IPRN in liver microsomes incubates were determined using LC-MS/MS. The enzyme kinetic and metabolic stability of PRN and IPRN were investigated by employing the optimized rat and human liver microsomes incubations. The Vmax and Km values were calculated using the nonlinear regression method. RESULTS The quanti?tative method showed good linearity within the range of 0.1-50.0 μmol · L-1 and was suitable for the assay in biological samples. The in vitro elimination was linear with the substrate concentrations lower than 1 μmol,the protein concentration within 0.5 g · L-1,and the incubation time within 40 min. The t1/2 values of PRN and IPRN in rat and human liver microsomes were 74.5,95.0,74.5 and 173.3 min, respectively. The Vmax values of PRN in rat and human liver microsomes were(1.140±0.080)μmol·min-1·g-1 protein,(0.620±0.060)μmol·min-1·g-1 protein,while Km values of PRN in rat and human liver microsomes were (12.9 ± 0.3)μmol · L- 1,(7.4 ± 1.3)μmol · L- 1,respectively. The Vmax values of IPRN in rat and human liver microsomes were(0.251±0.012)and(0.103±0.014)μmol·min-1·g-1 protein,while Km values of IPRN in rat and human liver microsomes were (3.0 ± 0.4)μmol · L-1,(3.4 ± 0.7)μmol · L-1,respectively. CONCLUSION The enzyme kinetic characters and metabolic stability of PRN and IPRN show species and chemical structures related differences. Interestingly,the metabolic eliminations of PRN and IPRN are similar in rats. However,the metabolic elimination of IPRN in humans involved in CYP enzymes may be much slower than that of PRN.

Research on detection method and clinical countermeasure of clopidogrel-resisted metabolism-related genes after interventional operation of coronary heart disease (CHD) / 中国医师杂志

Objective Study on cytochrome P450 (CYP) 2C19 gene single nucleotide polymorphism and the clinical prognosis of coronary heart disease (CHD) patients with percutaneous coronary intervention (PCI) after long-term use of clopidogrel.Methods A total of 150 cases of CHD patients was chosen prospectively between January 2013 and June 2014 who were hospitalized and PCI.All patients accepted dual antiplatelet therapy.Platelet aggregation rate and platelet aggregation inhibition rate were detected before taking the medicine and after PCI,which were used to classify the patients into clopidogrel-resistance groups (CR) and non-clopidogrel-resistance group (NCR).CYP2C19 gene single nucleotide polymorphism type was determined.The patients in CR group accepted clinical intervention countermeasures and NCR group was used as control,and postoperative recurrence angina and bleeding at the one year of operation were observed.Results About 24.67％ of patients with CHD with clopidogrel treatment,platelet aggregation rate cannot recover to normal.The correlation analysis showed CYP2C19* 2 carriers had a significantly higher platelet aggregation rate.Comprehensive analysis found that CYP2C19 * 2,long-term smoking,increased platelet count,and diabetes were the independent risk factors that platelet aggregation rate cannot recover to normal.No significant differences were found in primary end point,secondary end points,and bleeding events between CR group after clinical intervention countermeasures and NCR group.Conclusions CYP2C19 * 2,long-term smoking,increased platelet count,and diabetes are the independent risk factors that platelet aggregation rate cannot be developed to standard.Patients with clopidogrel resistance,the clinical intervention countermeasures to strengthen antiplatelet therapy can improve high platelet reactivity after PCI in CHD patients,and does not increase the risk of bleeding.

Efeitos da participação de esteroides-like provenientes da poluição atmosférica no epitélio das vias aéreas em camundongos machos e fêmeas / Effects of the participation of steroid-like compounds from air pollution in the airway epithelium of male and female mice

O epitélio nasal é a primeira porção do sistema respiratório a entrar em contato com o ambiente externo. Partículas da poluição do ar, principalmente os compostos orgânicos absorvidos, podem atuar como liberadores endócrinos. O receptor aril hidrocarboneto (AhR) é um importante competidor dos receptores de estrógeno-beta (ERbeta) que regulam a transcrição do gene para enzimas de metabolização xenobióticas (enzimas do citocromo P450). O objetivo deste estudo é identificar e quantificar ERbeta, AhR, CYP1A1, CYP1A2, CYP1B1 e o perfil de muco no epitélio nasal de camundongos machos e fêmeas em diferentes fases do ciclo estral. Camundongos BALB/c machos (n=32) e fêmeas (n=84) foram expostos ao ar ambiente e ao MP2,5 concentrado a 600 ug.m-³ em um concentrador de partículas ambientais (CPAs). As fêmeas foram divididas de acordo com as fases do ciclo estral: proestro, estro e diestro. O epitélio nasal foi avaliado por RT-PCR e imuno-histoquímica para análise de expressão de ERbeta (proteína), Erbeta-1 e Erbeta-2 (gene), AhR (proteína e gene) e Cyp1a1, Cyp1a2 and Cyp1b1 (gene). A quantificação de muco neutro - Periodic Acid Schiff's (PAS+) e ácido - Alcian Blue (AB+) foi avaliada por morfometria. As exposições foram realizadas durante 5 dias/semana, por 45 ± 55 dias. A expressão de Erbeta-2 RNAm apresentou diferenças em resposta à exposição ao CPAs (p=0,016), bem como uma diminuição em fêmeas, quando comparadas aos camundongos machos (p=0,036). A expressão de Cyp1b1 RNAm foi significantemente menor no grupo exposto ao CPAs, em relação ao grupo exposto ao ar ambiente nas fêmeas em diestro (p=0,036). A expressão de Erbeta foi aumentada no epitélio nasal de fêmeas em estro expostas ao CPAs (p=0,005) e a expressão de AhR foi menor em fêmeas em proestro expostas ao CPAs (p=0,048). A exposição ao CPAs levou ao aumento do conteúdo de muco ácido em camundongos machos (p=0,048), o qual diminuiu em fêmeas (p=0,040), quando comparados ao grupo ar ambiente. Este estudo mostrou...

The nasal epithelium is the first portion of the respiratory system to reach contact with the external environment. Air pollution particles, mainly the organic compounds absorbed into them, may act as endocrine releasers. The aryl hydrocarbon (AhR) receptor is an important competitor of estrogenic receptors-beta (ERbeta) that regulate transcription of gene coding for xenobiotic-metabolizing enzymes (cytochrome P450 enzymes). The aim of this study is to identify and quantify in the nasal epithelium of male and female mice in different estrous cycle phases related with ERbeta, AhR, CYP1A1, 1A2, 1B1 and the mucus profile. Male (n=32) and female (n=84) BALB/c mice were exposed to ambient air and PM2.5 concentrated at 600 ug.m-³ in an ambient particle concentrator with a particulate matter diameter of 2.5 um (PM2.5). Females were subdivided in three estrous cycles: proestrus, estrus and diestrus. Nasal epithelium was evaluated through RT-PCR and immunohistochemistry for the expression of ERbeta (protein), Erbeta-1 and Erbeta-2 (gene expression), AhR (protein and gene expression) and Cyp1a1, Cyp1a2 and Cyp1b1 (gene expression). Morphometry was applied for evaluation of mucus profile: acid - Alcian Blue (AB+) and neutral - Periodic Acid Schiff's (PAS+). Exposure happened for 5 days/week, for 45 ± 55 days. There were differences in Erbeta-2 mRNA in response to exposition to CPAs (p=0.016), and a significant decrease in female compared male mice (p=0.036). Cyp1b1 mRNA was significantly smaller in the CPAs-exposed group compared with the ambient air group in diestrus female mice (p=0.036). The ERbeta expression increased in the nasal epithelium of CPAs-exposed females in the estrus cycle (p=0.005), and the AhR expression decreased in the proestrus cycle of CPAs-exposed females (p=0.048). The exposure to the CPAs led to an increase in the acidic content of mucus in male mice (p=0.048), and decreased in female mice (p=0.040), compared to the ambient air group. This...