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New Alleles of Rice ebisu dwarf (d2) Mutant Show both Brassinosteroid-Deficient and -Insensitive Phenotypes  [PDF]
Tomoaki Sakamoto, Yoichi Morinaka, Hidemi Kitano, Shozo Fujioka
American Journal of Plant Sciences (AJPS) , 2012, DOI: 10.4236/ajps.2012.312208
Abstract: ebisu dwarf (d2) is a mutant caused by mutation in a rice brassinosteroid biosynthetic enzyme gene, CYP90D2/D2, thereby conferring a brassinosteroid-deficient dwarf phenotype. Three newly isolated d2 alleles derived from a Nippon- bare mutant library (d2-3, d2-4, and d2-6) produced more severe dwarf phenotypes than the previously characterized null allele from a Taichung 65 mutant library, d2-1. Linkage analysis and a complementation test clearly indicated that the mutant phenotypes in d2-6 were caused by defects in CYP90D2/D2, and exogenous treatment with brassinolide, a bioactive brassinosteroid, rescued the dwarf phenotype of three Nipponbare-derived d2 mutants. However, the content of endogenous bioactive brassinosteroid, castasterone, and the expression of brassinosteroid-response genes indicated that partial suppression of the brassinosteroid response in addition to a brassinosteroid deficiency has occurred in the Nipponbare-derived d2 mutants. Based on these results, we discuss the possibility that wild-type Nipponbare has some defects in an unknown factor or factors related to the brassinosteroid response in rice.
Application of Precision-Cut Rat Liver Slice to Study the Influence of Monocrotaline, Tussilago farfara Alkaloids on the Expression of Cytochrome P450 Enzymes  [PDF]
Hailin Wang, Lianqiang Hui, Chun Li, Ting Liu, Chang’an Yu, Chunyu Cao, Ran Hao, Yi Zhang
Health (Health) , 2016, DOI: 10.4236/health.2016.84039
Abstract: Precision-cut liver slice has been successfully used to study the mechanism of drug-induced hepatotoxicity, the prediction of liver toxicity, the discovery of early hepatic toxicity biomarker and the metabolism of drug in liver. We detected the expression of CYP3A4, CYP2B1 + CYP2B2 and CYP2E1 in precision-cut liver slice after co-cultured with monocrotaline or Tussilago farfara alkaloids to investigate the hepatotoxicity mechanism of those drugs. After co-culturing with monocrotaline or Tussilago farfara alkaloids for 6 hours, the expression of CYP3A4 in the microsome of precision-cut liver slices was detected by Western blot, and the expressions of CYP2B1 + CYP2B2 and CYP2E1 were detected by immunofluorescence. The results showed that monocrotaline induced the expression of CYP3A4 and CYP2B1 + CYP2B2, and Tussilago farfara alkaloids obviously up-regulated the expression of CYP2E1 and CYP3A4. Thus, we conclude that the up-regulation of CYP3A4, CYP2B1 + CYP2B2 and CYP2E1 may be one of the toxic mechanisms of liver injury of those drugs.
e-PKGene: A knowledge-based research tool for analysing the impact of genetics on drug exposure
Houda Hachad, Casey Overby, Sophie Argon, Catherine K Yeung, Isabelle Ragueneau-Majlessi, René H Levy
Human Genomics , 2011, DOI: 10.1186/1479-7364-5-5-506
Abstract: Differences in drug response among patients are common, often leading to challenges in optimising a dosage regimen for an individual patient. Genetic factors have long been known to cause interindividual differences in the pharmacokinetics, efficacy and adverse events of a number of drugs,[1] and drug metabolising enzymes have been shown to be the greatest source of pharmacogenetic (PGx) variability identified to date. It is estimated that over half of the ~170 genes with products affecting drug disposition are polymorphic,[2] and clinically important polymorphisms have been identified for most major enzymes involved in both phase I and phase II drug metabolism [3]. More recently, the polymorphic variability of several transporter proteins, such as the hepatic uptake transporter, organic anion transporter polypeptide 1B1 (OATP1B1), has been shown to have an impact on the exposure to, and safety of, widely prescribed drugs [4]. Thus, incorporating the knowledge gained from PGx research to make decisions in drug development and clinical care has the potential to increase the safety and efficacy of drug treatment, and is central to the strategies of personalised medicine [5]. In spite of current efforts to incorporate the use of PGx information in drug development, clinical practice and in making cost-effective healthcare decisions, however, information uptake remains low. Translational research is required to move PGx discoveries effectively to evidence-based application in these areas. Translational research has been described as having four iterative phases with feedback loops, to allow integration of new knowledge [6]. Phase 1 (T1) and Phase 2 (T2) translational research informs the development of clinical interventions and evidence-based guidelines; Phase 3 (T3) research assesses the implementation of guidelines in health practice; and Phase 4 (T4) research evaluates the health outcomes of changes in practice following the implementation of guidelines [6]. All pha
Influence of paraoxonase-1 Q192R and cytochrome P450 2C19 polymorphisms on clopidogrel response
Kreutz RP, Nystrom P, Kreutz Y, Miao J, Desta Z, Breall JA, Li L, Chiang C, Kovacs R, Flockhart DA, Jin Y
Clinical Pharmacology: Advances and Applications , 2012, DOI: http://dx.doi.org/10.2147/CPAA.S27822
Abstract: fluence of paraoxonase-1 Q192R and cytochrome P450 2C19 polymorphisms on clopidogrel response Original Research (3350) Total Article Views Authors: Kreutz RP, Nystrom P, Kreutz Y, Miao J, Desta Z, Breall JA, Li L, Chiang C, Kovacs R, Flockhart DA, Jin Y Published Date February 2012 Volume 2012:4 Pages 13 - 20 DOI: http://dx.doi.org/10.2147/CPAA.S27822 Received: 01 November 2011 Accepted: 05 December 2011 Published: 20 February 2012 Rolf P Kreutz1,2, Perry Nystrom2, Yvonne Kreutz2, Jia Miao2, Zeruesenay Desta2, Jeffrey A Breall1, Lang Li2, ChienWei Chiang2, Richard Kovacs1, David A Flockhart2, Yan Jin2 1Krannert Institute of Cardiology, 2Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA Background: The metabolic activation of clopidogrel is a two-step process. It has been suggested that paraoxonase-1 (PON1) is a rate-limiting enzyme in the conversion of 2-oxo-clopidogrel to an active thiol metabolite. Conflicting results have been reported in regard to (1) the association of a common polymorphism of PON1 (Q192R) with reduced rates of coronary stent thrombosis in patients taking clopidogrel and (2) its effects on platelet inhibition in patient populations of European descent. Methods: Blood samples from 151 subjects of mixed racial background with established coronary artery disease and who received clopidogrel were analyzed. Platelet aggregation was determined with light transmittance aggregometry and VerifyNow P2Y12 assay. Genotyping for cytochrome P450 2C19 (CYP2C19)*2 and *3 and PON1 (Q192R) polymorphisms was performed. Results: Carriers of CYP2C19*2 alleles exhibited lower levels of platelet inhibition and higher on-treatment platelet aggregation than noncarriers. There was no significant difference in platelet aggregation among PON1 Q192R genotypes. Homozygous carriers of the wild-type variant of PON1 (QQ192) had similar on-treatment platelet reactivity to carriers of increased-function variant alleles during maintenance clopidogrel dosing, as well as after administration of a clopidogrel 600 mg loading dose. Conclusion: CYP2C19*2 allele is associated with impaired platelet inhibition by clopidogrel and high on-treatment platelet aggregation. PON1 (Q192R) polymorphism does not appear to be a significant determinant of clopidogrel response.
DrugMetZ DB: an anthology of human drug metabolizing Chytochrome P450 enzymes
Tresha Remya,Shanthi Nagarajan
Bioinformation , 2006,
Abstract: Understandings the basics of Cytochrome P450 (P450 or CYP) will help to discern drug metabolism. CYP, a super-family of heme-thiolate proteins, are found in almost all living organisms and is involved in the biotransformation of a diverse range of xenobiotics, therapeutic drugs and toxins. Here, we describe DrugMetZ DB, a database for CYP metabolizing drugs. The DB is implemented in MySQL, PHP and HTML.
Identification and classification of detoxification enzymes from Culex quinquefasciatus (Diptera: Culicidae)
BP Niranjan Reddy,B Prasad Rao,GBKS Prasad,K Raghavendra
Bioinformation , 2012,
Abstract: Molecular characterization of the insecticide resistance has become a hot research topic ever since the first disease transmitting arthropod (Anopheles gambiae) genome sequence has unveiled in 2002. A recent publication of the Culex quinquefasciatus genome sequence has opened up new opportunities for molecular and comparative genomic analysis of multiple mosquito genomes to characterize the insecticide resistance. Here, we utilized a whole genome sequence of Cx. quinquefasciatus to identify putatively active members of the detoxification supergene families, namely cytochrome P450s (P450s), glutathione-S-transferases (GSTs), and choline/carboxylesterases (CCEs). The Culex genome analysis revealed 166 P450s, 40 GSTs, and 62 CCEs. Further, the comparative genomic analysis shows that these numbers are considerably higher than the other dipteran mosquitoes. These observed species-specific expansions of the detoxification super gene family members endorse the popular understanding of the involvement of these gene families in protecting the organism against multitudinous classes of toxic substances during its complex (aquatic and terrestrial) life cycle. Thus, the generated data set may provide an initial point to start with to characterize the insecticide resistance at a molecular level which could then lead the development of an easy to use molecular marker to monitor the incipient insecticide resistance in field environs.
Long-term effect of copper with sublethal dose on cytochrome P450 and antioxidant enzyme activities of earthworms
亚致死剂量铜对蚯蚓P450酶和抗氧化酶活性的长期影响
YANG Xiaoxi,ZHANG Wei,CAO Xiufeng,LIU Yang,JI Puhui,SONG Yufang,
杨晓霞,张薇,曹秀凤,刘杨,吉普辉,宋玉芳
环境科学学报 , 2012,
Abstract: 以赤子爱胜蚓(Eisenia fetida)为供试生物,通过人工污染草甸棕壤的方法,研究了暴露于含有亚致死剂量Cu(100、200、300、400 mg·kg-1)的土壤中8周时间内蚯蚓体内细胞色素P450含量、谷胱甘肽转移酶(GST)、超氧化物歧化酶(SOD)及过氧化氢酶(CAT)活性的变化.结果显示,各指标在暴露1周时均无显著变化,但在第8周时各指标均受到显著抑制.P450含量在100 mg·kg-1剂量水平下暴露2周时表现出显著的诱导效应;GST、SOD和CAT活性则均在第3周开始表现出显著的诱导效应,且SOD和CAT在100 mg·kg-1剂量下即出现诱导现象,而GST则在200 mg·kg-1剂量下显现诱导现象.暴露时间大于4周时,P450含量及GST活性开始表现出抑制效应,SOD及CAT活性则在暴露大于6周后显现抑制效应.以上指标对污染物的响应模式为:无显著变化→诱导→抑制.铜是蚯蚓生长的必需元素,蚯蚓自身对Cu的适应机制,以及对铜的长期摄取能危害蚯蚓正常代谢可解释上述响应模式产生的原因.但各指标在对毒性的响应敏感性上存在差异,其中,P450响应最为敏感,而SOD、CAT最不敏感.因此,在生态毒性诊断时,应选择不同指标作为一套指标体系相互补充,以增强污染诊断的灵敏性及长期诊断性.
Effects of quinolones on activity of hepatic drug-metabolizing enzymes in Paralichthys olivaceus
喹诺酮类药物对牙鲆肝药物代谢酶活性的影响
HAN Hua,LI Jian,Li Ji-tao,HAN Xian-qin,Chen Ping,
韩华,李健,李吉涛,韩现芹,陈萍
海洋科学 , 2009,
Abstract: In order to observe the difference of effects of quinolones on the activity of drug-metabolism(cytochrome P-450),we studied the effects of quinolones(FQ)on the activities of APND,ERND and EROD in the liver of flounders(Paralichthys olivaceus).The results showed that the activities of APND,ERND and EROD in the S_9 mix were inhibited by the three kinds of quinolones on the different degrees,where enrofloxacin and norfloxacin treated groups had a very significant decrease on the activities of APND,ERND and EROD compared to the control group(P＜0.01),while flumequine treated group only decreased the activity of EROD very significantly(P＜0.01),and had a significant decrease on the activities of APND and ERND.
Antioxidant Activity of New Aramide Nanoparticles Containing Redox-Active N-phthaloyl Valine Moieties in the Hepatic Cytochrome P450 System in Male Rats
Hammed H. A. M. Hassan,Sabah G. El-Banna,Amel F. Elhusseiny,El-Sayed M. E. Mansour
Molecules , 2012, DOI: 10.3390/molecules17078255
Abstract: We report the synthesis of aramide nanoparticles containing a chiral N-phthaloyl valine moiety and their antioxidant activities on hepatic contents of cytochrome P450, amidopyrene N-demethylase, aniline-4-hyroxylase and induced the hepatic content of cytochrome b5 and nicotinamide adenine dinucleotide phosphate (NADPH) cytochrome C-reductase. Polymers were obtained as well-separated spherical nanoparticles while highly aggregated particles via H-bonding organization of the aramide-containing pyridine led to a thin layer formation. The effects of the nanoparticles and CCl4 on enzyme activities and thiobarbituric acid reactive substances (TBARS) levels of male rat liver were studied. Pretreatments of rats with the polyamides prior to the administration of CCl4 decreased the hepatic content of the tested enzymes. Doses reduced the toxic effects exerted by (？CCl3) upon the liver through inhibition of the cytochrome P450 system. Inhibition of such metabolizing enzymes could reduce the carcinogenic effects of chemical carcinogens.
A useful tool for drug interaction evaluation: The University of Washington Metabolism and Transport Drug Interaction Database
Houda Hachad, Isabelle Ragueneau-Majlessi, René H Levy
Human Genomics , 2010, DOI: 10.1186/1479-7364-5-1-61
Abstract: Adverse drug reactions (ADRs) remain one of the leading causes of morbidity and mortality in healthcare. In January 2000 the Institute of Medicine reported that between 44,000 and 98,000 deaths occur annually from medical errors in American hospitals [1]. Of this total, an estimated 7,000 deaths occur due to ADRs. It is estimated that drug-drug interactions (DDIs) represent 3-5 per cent of all in-hospital medication errors and that they are also an important cause of patient visits to emergency departments [2] Among the factors that contribute to the occurrence of a DDI are patient age, number and type of concomitant medications and disease stage. In recent years, while healthcare providers have been offered access to and have benefitted from numerous drug information tools that have provided them with guidance on how drugs can be co-administered, researchers within the drug development community have had access to a more limited portfolio of data repositories. These scientists need to browse the vast literature for primary scientific data (ie datasets on metabolic isozymes, transporters, substrates, inducers, and inhibitors) that will provide them with context for their research findings and help with their drug interaction programme.The University of Washington's Metabolism and Transport Drug Interaction Database (DIDB; http://www.druginteractioninfo.org webcite) was initially designed with extensive input from scientists from pharmaceutical companies and was tailored to their various needs. Later, the tool capabilities were expanded and its use was extended to other groups (Table 1).The database contains in vitro and in vivo kinetics information for drug-metabolising enzymes and transporters, pharmacokinetics parameters/pharma-codynamic measures and side effects reported in clinical drug interaction studies. Each dataset integrates both the experimental design and the primary results. The database can be searched not only by main concepts in the field of drug int
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