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Transposable elements are enriched within or in close proximity to xenobiotic-metabolizing cytochrome P450 genes
Song Chen, Xianchun Li
BMC Evolutionary Biology , 2007, DOI: 10.1186/1471-2148-7-46
Abstract: Twelve novel transposons, including LINEs (long interspersed nuclear elements), SINEs (short interspersed nuclear elements), MITEs (miniature inverted-repeat transposable elements), one full-length transib-like transposon, and one full-length Tcl-like DNA transpson, are identified from the alleles of the six H. zea P450 genes. The twelve transposons are inserted into the 5'flanking region, 3'flanking region, exon, or intron of the six environment-adaptation P450 genes. In D. melanogaster, seven out of the eight Drosophila P450s (CYP4E2, CYP6A2, CYP6A8, CYP6A9, CYP6G1, CYP6W1, CYP12A4, CYP12D1) implicated in insecticide resistance are associated with a variety of transposons. By contrast, all the five Drosophila P450s (CYP302A1, CYP306A1, CYP307A1, CYP314A1 and CYP315A1) involved in ecdysone biosynthesis and developmental regulation are free of TE insertions.These results indicate that TEs are selectively retained within or in close proximity to xenobiotic-metabolizing P450 genes.All organisms must adapt to their environments composed of biotic and abiotic factors to survive and reproduce. This requires organisms to allocate a substantial portion of their genomes to encode environment response genes that can be defined as those involved in interactions external to the organisms [1]. Examples of environmental response genes are those involved in pathogenesis or virulence (in pathogens), biosynthesis of toxic compounds (in plants), and detoxification (in animals). To cope with the ever-changing environment, organisms are also required to have greater genomic plasticity in the environmental response genes so that novel adaptive genomic changes (mutations) are available for natural selection.Although there may be a few environmental stress factors such as UV radiation and mutagenic xenobiotics that can directly cause genomic changes, the majority of environmental factors act as pure selection agents rather than mutagens. Therefore, the genomic plasticity necessary for co
Hepatic CYP Isoforms and Drug-Metabolizing Enzyme Activities in Broiler Chicks  [PDF]
Joseph C. Kawalek,Michael J. Myers,Karyn D. Howard,Dorothy E. Farrell
International Journal of Poultry Science , 2006,
Abstract: Day-old chicks were raised for four - six weeks in pens using different bedding materials (wire, paper, corn cobs, hardwood, rice hulls, cedar, and pine) to determine if these beddings have any effect on hepatic drug metabolizing enzyme activities, cytochrome P450 isoforms, and the disposition of enrofloxacin, a drug previously approved for use in chickens. Cytochrome P450 (CYP) isoforms from the major P450 isoform families (1A, 2A, 2B, 2C, 2D, 2E, 3A, and 4A) and their corresponding hepatic drug metabolizing enzyme activities were measured in subcellular fractions obtained from 4-and 5-week-old birds. Five week-old birds were treated with medicated water containing Baytril at 50 ppm enrofloxacin for five consecutive days and then withdrawn for two days prior to sacrifice. There were no significant differences in P450-mediated reactions or levels of CYP isoforms between any of the different test groups. The marker residue for enrofloxacin was barely detectable in the marker tissue (breast muscle) of the treated birds. The major metabolites of enrofloxacin, namely, ciprofloxacin, desethylenyl-enrofloxacin, and desethylenyl ciprofloxacin, were detectable in extracts of liver homogenates of the treated birds. However, the levels were below the level of quantification.
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.
Avian Cytochrome P450 (CYP) 1-3 Family Genes: Isoforms, Evolutionary Relationships, and mRNA Expression in Chicken Liver  [PDF]
Kensuke P. Watanabe, Yusuke K. Kawai, Yoshinori Ikenaka, Minami Kawata, Shin-Ichi Ikushiro, Toshiyuki Sakaki, Mayumi Ishizuka
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0075689
Abstract: Cytochrome P450 (CYP) of chicken and other avian species have been studied primarily with microsomes or characterized by cloning and protein expression. However, the overall existing isoforms in avian CYP1-3 families or dominant isoforms in avian xenobiotic metabolism have not yet been elucidated. In this study, we aimed to clarify and classify all of the existing isoforms of CYP1-3 in avian species using available genome assemblies for chicken, zebra finch, and turkey. Furthermore, we performed qRT-PCR assay to identify dominant CYP genes in chicken liver. Our results suggested that avian xenobiotic-metabolizing CYP genes have undergone unique evolution such as CYP2C and CYP3A genes, which have undergone avian-specific gene duplications. qRT-PCR experiments showed that CYP2C45 was the most highly expressed isoform in chicken liver, while CYP2C23b was the most highly induced gene by phenobarbital. Considering together with the result of further enzymatic characterization, CYP2C45 may have a dominant role in chicken xenobiotic metabolism due to the constitutive high expression levels, while CYP2C23a and CYP2C23b can be greatly induced by chicken xenobiotic receptor (CXR) activators. These findings will provide not only novel insights into avian xenobiotic metabolism, but also a basis for the further characterization of each CYP gene.
Changes in mRNA Expression and Activity of Xenobiotic Metabolizing Enzymes in Livers from Adjuvant-Induced Arthritis Rats  [PDF]
Atsushi Kawase, Syoko Wada, Masahiro Iwaki
Pharmacology & Pharmacy (PP) , 2013, DOI: 10.4236/pp.2013.46069
Abstract: Pathophysiological changes in human patients and in animal models of infection or inflammation are associated with alterations in the production of numerous liver-derived proteins including metabolizing enzymes. In this study, the effects of adjuvant-induced arthritis (AA) in rats on the levels of mRNA and activity of hepatic xenobiotic metabolizing enzymes were determined during the inflammatory response. The mRNA levels of cytochrome P450 (CYP) 1A2, CYP2C12, CYP2D1, CYP2D2, and CYP3A1 were significantly decreased compared with control levels in almost all phases of inflammation. A reduction in the activity of CYP2C and CYP3A, which are abundantly expressed in the liver, was also observed. For phase II metabolizing enzymes, mRNA levels of uridine 5’-diphospho-glucuronosyltransferase (UGT) 1A1, UGT1A6, sulfotransferase (SULT) 2A1, and glutathione S-transferase 2 were significantly decreased compared with control levels. However, the mRNA levels of UGT2B and SULT1A1 returned to control levels during the subacute (7 d after adjuvant treatment) and chronic (21 d after adjuvant treatment) phases although these levels decreased during the acute (3 d after adjuvant treatment) phase. These results suggest that the effects of inflammation on the expression of xenobiotic metabolizing enzymes differ depending on the isoform of the enzyme and could affect the pharmacokinetics of each substrate.
The Cytochrome P450 Homepage
David R Nelson
Human Genomics , 2009, DOI: 10.1186/1479-7364-4-1-59
Abstract: The Homepage http://drnelson.utmem.edu/CytochromeP450.html webcite grew out of a need for unlimited space to present nomenclature and annotation information on cytochrome P450 sequences. The 1993 cytochrome P450 nomenclature paper [1] was 51 pages long and was the last dedicated P450 nomenclature publication before the website was opened in February 1995. That paper had 12 authors, all well known in the field. Multi-author agreement was the strategy of Daniel W. Nebert, who with Frank J. Gonzalez launched the standardised cytochrome P450 nomenclature system in 1987, [2] with follow-ups in 1989 [3] and 1991. [4] The P450 nomenclature prior to this system was fragmented and difficult, with many laboratories having their own shorthand notation for P450s, often based on molecular weight or migration position on gels. For example, CYP2A1 had six different names in the literature. The new CYP nomenclature was one of the first systematic nomenclatures for a protein superfamily and it became adopted for use by many other groups struggling with the rapid expansion of sequence data in the 1980s.The Cytochrome P450 Homepage was started on a desktop Macintosh Quadra 650, running WebStar as the server software. I believe MOSAIC was the web browser at that time. The 1993 paper had 221 P450 genes and 12 pseudogenes listed. [1] On 10th October, 1995 I gave a talk at the Third International Symposium on Cytochrome P450 Biodiversity in Woods Hole, Massachusetts, titled: '450 Cytochrome P450s', so the number of CYPs had doubled in less than two years. I posted a sequence alignment on a wall at that meeting with all the non-confidential P450s. This occupied about a 2 × 3 metre squared space, and everyone wanted to come to see their own sequences.Clearly, publications could not include such large alignments, and there was no space to discuss individual sequences. Even 51-page papers could only include long tables to list the genes. A website was the solution. The initial web pages were
Fungal cytochrome P450 database
Jongsun Park, Seungmin Lee, Jaeyoung Choi, Kyohun Ahn, Bongsoo Park, Jaejin Park, Seogchan Kang, Yong-Hwan Lee
BMC Genomics , 2008, DOI: 10.1186/1471-2164-9-402
Abstract: The Fungal Cytochrome P450 Database (FCPD) archives genes encoding P450s in the genomes of 66 fungal and 4 oomycete species (4,538 in total) and supports analyses of their sequences, chromosomal distribution pattern, and evolutionary histories and relationships. The archived P450s were classified into 16 classes based on InterPro terms and clustered into 141 groups using tribe-MCL. The proportion of P450s in the total proteome and class distribution in individual species exhibited certain taxon-specific characteristics.The FCPD will facilitate systematic identification and multifaceted analyses of P450s at multiple taxon levels via the web. All data and functions are available at the web site http://p450.riceblast.snu.ac.kr/ webcite.Cytochrome P450 is the collective name for a super family of heme-containing monooxygenases. P450 enzymes not only participate in the production of diverse metabolites but also play critical roles in organism's adaptation to specific ecological and/or nutritional niches by modifying potentially harmful environmental chemicals. In fungi, P450 enzymes have contributed to exploration of and adaptation to diverse ecological niches [1,2].Rapidly accumulating genome sequences from diverse fungal species, including more than 80 species with more currently being sequenced [3], offer opportunities to study the genetic and evolutionary mechanisms underpinning different fungal life styles at the genome level [4-7]. To support such studies with the focus on cytochrome P450s, we constructed a new platform named as the Fungal Cytochrome P450 Database (FCPD), which archives P450s in most sequenced fungal and oomycetes species and allows comparison of the archived data with previously published datasets, such as the Cytochrome P450 Engineering Database [8], a manually curated P450 database at http://drnelson.utmem.edu/CytochromeP450.html webcite (referred as the Nelson's P450 database herein), and P450 datasets derived from extensive phylogenetic analys
Optimization of the Bacterial Cytochrome P450 BM3 System for the Production of Human Drug Metabolites  [PDF]
Giovanna Di Nardo,Gianfranco Gilardi
International Journal of Molecular Sciences , 2012, DOI: 10.3390/ijms131215901
Abstract: Drug metabolism in human liver is a process involving many different enzymes. Among them, a number of cytochromes P450 isoforms catalyze the oxidation of most of the drugs commercially available. Each P450 isoform acts on more than one drug, and one drug may be oxidized by more than one enzyme. As a result, multiple products may be obtained from the same drug, and as the metabolites can be biologically active and may cause adverse drug reactions (ADRs), the metabolic profile of a new drug has to be known before this can be commercialized. Therefore, the metabolites of a certain drug must be identified, synthesized and tested for toxicity. Their synthesis must be in sufficient quantities to be used for metabolic tests. This review focuses on the progresses done in the field of the optimization of a bacterial self-sufficient and efficient cytochrome P450, P450 BM3 from Bacillus megaterium, used for the production of metabolites of human enzymes. The progress made in the improvement of its catalytic performance towards drugs, the substitution of the costly NADPH cofactor and its immobilization and scale-up of the process for industrial application are reported.
Change in mRNA Expression of Human Cytochrome P450 by Gold Nanoparticles  [PDF]
L. Wangcharoenrung,W. Warisnoicharoen
Journal of Biological Sciences , 2011,
Abstract: The effect of gold nanoparticles (AuNPs) on the mRNA expression of cytochrome P450 (CYP) enzymes as main metabolizing enzymes has been investigated. Citrate-stabilized AuNPs (AuCi) and polyethyleneimine-stabilized AuNPs (AuPEI) were synthesized and characterized for sizes and surface charges using Transmission Electron Microscopy (TEM) and zeta potential measurement, respectively. The induction effect of AuNPs on mRNA expression of CYPs 1A2, 2C9, 2E1 and 3A4 in human hepatocellular carcinoma (HepG2) cell line was measured with quantitative real time PCR method. The results showed that AuCi and AuPEI had average particle diameters of 15.002.77 and 5.021.81 nm and zeta potential of -40.601.22 and 8.101.59 mV, in orderly. After 48 h exposure to the AuCi (1 and 10 M) and AuPEI (0.1 and 1 M), the CYP1A2 mRNA level in HepG2 cells was over 2-fold induction. Moreover, an addition of 1 M AuPEI to 10 M a-naphthoflavone as CYP1A2 inducer caused the level of CYP1A2 mRNA to be significantly higher (p=0.05) than that induced by a-naphthoflavone alone. The study shows that the mRNA expression change is likely to depend upon the size and charge of AuNPs. The smaller and positively charged AuPEI promote the cellular penetration, thus probably potentiating of CYP mRNA transcription.
Antioxidant Activity of New Aramide Nanoparticles Containing Redox-Active N-phthaloyl Valine Moieties in the Hepatic Cytochrome P450 System in Male Rats  [PDF]
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.
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