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Dissertations / Theses on the topic 'Cytochrome P-450'

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Published: 4 June 2021

Last updated: 28 July 2024

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1

Clarke, Stephen Edward. "Characterisation of housefly cytochrome P-450." Thesis, University of Surrey, 1989. http://epubs.surrey.ac.uk/847312/.

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The cytochrome P-450 dependent monooxygenase activity in a 'wild type' susceptible strain of housefly was studied. Catalytic activities were identified that demonstrated that the housefly cytochrome P-450 was capable of similar catalytic functions as those described for higher animals. Although several specific activities were lower than in mammalian species, benzphetamine N-demethylation was comparable and there was higher constitutive activity toward lauric acid than is observed in rat hepatic microsomes. The inducing agent phenobarbital increased both total cytochrome P-450 content and the benzphetamine N-demethylase specific activity. The high constitutive activity for fatty acids was induced by the hypolipidaemic drug clofibrate, specifically inducing the w-hydroxylase activity. The substrate specificity toward lauric acid extended equally to myristic and palmitic acid. Housefly microsomal cytochrome P-450 also metabolised the unsaturated fatty acid, arachidonic acid, the w-hydroxy-lation again inducible by clofibrate pretreatment. The w-hydroxylation of these fatty acids appeared to be a well-coupled reaction, a property that also appeared to be exhibited by the rat hepatic w-hydroxylase. The housefly fatty acid hydroxylation showed certain similarities to that in the rat, both in the specificity for w-hydroxylation and in the result of induction by clofibrate. Structural comparison to cytochrome P-450IVA1, IIB1 and IA1 was made by Western blot analysis with polyclonal antibodies raised to these rat hepatic isoenzymes. Housefly cytochrome P-450 shared few, if any, common epitopes with these rat isoenzymes, nor did these antibodies inhibit housefly cytochrome P-450 dependent monooxygenase activity. Cytochrome P-450 from clofibrate-pretreated housefly microsomes was partially purified by affinity chromatography. The cytochrome P-450 had a specific content of 5. 7nmol.mg-1 and a monomeric molecular weight of 52,000 daltons and a reduced carbon monoxide difference spectrum absorbance maxima at 448nm. In a reconstituted system, this preparation exhibited activity toward lauric acid and to a lesser extent arachidonic acid in each case w-hydroxylated products predominated. This is the first example of a purification of an insect cytochrome P-450 multiple form with a defined product reaction.

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2

Jones, Barry Christopher. "Cytochrome P-450 mediated N-dealkylation." Thesis, University of Surrey, 1989. http://epubs.surrey.ac.uk/844436/.

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An investigation into the physico-chemical and molecular mechanical properties of tertiary amines which predispose them to rapid metabolism by cytochrome P-450 has been undertaken. A series of tertiary amines based on the common 2-(2,4-dichlorophenoxy)-N-methylethanamine moiety was synthesised with different substituent groups which changed the lipophilicity, size, polarity and electronic configuration. The substituent groups employed included n-alkyl, branched alkyl, aromatic, unsaturated, and oxygenated moieties. The design of the molecules was centred around an N~methyl group which was shown to be the major site of metabolism in a selected series of the molecules. The rates of N-demethylation were used as the index by which the effect of changing the substituent group was assessed. Studies using chemical inducers and inhibitors of cytochrome P-450 indicated that the hepatic microsomal fraction obtained from rats that had been pretreated with phenobarbital was the most effective biological system for the study of the rate of metabolism of these compounds. Further investigations using purified cytochrome P450 IIB4 in a reconstituted system showed that this particular isozyme of cytochrome P-450 was capable of supporting the metabolism of these compounds indicating that in the rat hepatic microsomes it was cytochrome P450 IIB1 which was mediating the compounds' metabolism. Various physico-chemical properties including lipophilicity, pKa and the octanol/water partition coefficient at pH 7.4 (log D) were determined for each of the compounds. The X-ray crystal structures of two of the molecules were solved to provide co-ordinates that were used in the determination of various molecular mechanical parameters such as the partial charges on the atoms in the molecules. The physico-chemical parameters were correlated with biological parameters obtained from both hepatic microsomal and purified cytochrome P450 IIB4 in a reconstituted system. The biological parameters determined were the binding affinity (K3, K3 and K4), the substrate-induced cytochrome P-450 spin state change (% HS and K2), Vmax and Km. No correlation was found between these parameters derived from the different biological systems. This may have been a result of changes in the tertiary structure of the enzyme brought about- as a result of the purification process or it may have been due to differences in the primary structures of cytochrome P450 IIB1 and IIB4. Quantitative structure-activity relationships derived between these sets of parameters for the microsomal system indicated that increasing size and lipophilicity produced stronger binding of the substrate to the enzyme, however, this gave no information about the orientation of the molecule in the enzyme's active site. A correlation was found for Km which indicated that the electronic structure of the molecules may influence the orientation that the molecule adopts in the active site of the enzyme. No correlations were found for Vmax, however the ratioVmax/Km produced a number of correlations which indicated that this parameter was dependent on the electron density on the nitrogen atom and the electronic influence of the substituent group on the nitrogen atom. Very few correlations were found for the biological parameters determined using purified cytochrome P450 IIB4 in a reconstituted system. Those that were obtained went a little way in supporting the suggestion that compounds bind to cytochrome P-450 via a hydrophobic interaction.

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3

Boitrel, Bernard. "Modeles d'hemoproteines : hemoglobine et cytochrome p-450." Paris 6, 1989. http://www.theses.fr/1989PA066059.

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4

Krause, Maren. "Genetische Variabilität des Cytochrom P 450- Systems im Zusammenhang mit einem erhöhten Risiko für Rheumatoide Arthritis." Doctoral thesis, Universitätsbibliothek Leipzig, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-143774.

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Rheumatoid Arthritis is a chronic inflammatory systemic disease and is one of the autoimmune diseases. In this study, nine candidate genes of the cytochrome P450 system have been analyzed to determine their possible association with the formation of RA. These genes are: CYP1A1, CYP1B1, CYP2B6, CYP2E1, CYP2C9, CYP2D6, CYP2A6, CYP2C19 and CYP3A4.Within these genes, 21 single nucleotide polymorphism, SNPs, in 300 French Caucasian individuals (100 RA trio families) were genotyped using single-base-extensions, SBE, in a mass spectrometric analysis by MALDI-TOF-MS (matrix-assisted Laser Desorption/ Ionization-time-of-flight mass spectometry). The selection of the examined genes was carried out taking into account known associations with RA or other autoimmune disease, as well as known functional variants. Decisive were also the location of the gene and genetic variability. The results of genotyping were used to study polymorphisms on their association with Rheumatoid Arthritis. The statistical analyzes of CYP2C9 rs1799853 (3011) showed, in the family-based single-marker test, a lower transmission (TDT p-value 0.021) for the rare allele (3011-a). The case-control allelic based test shows, there is a protective effect (Odds Ratio 0.58). In the case-control-based genotypic test this issue could be reproduced (p-value 0.046). For the rare allele of the CYP2A6 rs1801272 (3022-a) the family-based single-marker test shows a lower transmittance (TDT p-value 0.037). The case-control allelic based test shows a protective effect of this allele (Odds Ratio 0.32). In the case-control-based genotypic test a statistical trend to protective behavior of this allele occurs. SNPs with predicted functional relevance showed no statistical abnormalities in the studied cohort. In genome-wide studies, the results could not be tracked, at least at the gene level weak associations could be detected. The results of this study should be to replicate in one second independent cohort. Care should be taken specifically to xenobiotic stress, such as job stress, smoking, and medication. In subsequent studies more SNPs of the candidate genes could also genotyped in order to verify the genetic variability with reference to of the haplotypes in more detail. Should the above-mentioned associations be confirmed, functional studies on different gene expression or altered metabolite spectrum are highly interesting.

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5

Chassagne, Philippe. "Expression des cytochromes P-450 pancréatiques." Montpellier 1, 1994. http://www.theses.fr/1994MON11135.

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6

Zhao, Jin 1975. "Investigations of the biocatalytic activity of human P450 2D6." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111940.

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The cytochrome P450 enzymes (CYPs) are very attractive biocatalysts because of their ability to regio- and stereo-selectively catalyze the insertion of a single atom of molecular oxygen into inactivated C-H bonds. There are many drawbacks, however, limiting the use of these enzymes in organic synthesis, including the need for expensive cofactors, low stability, and low tolerance to organic solvents. The goal of this thesis was to overcome some of these drawbacks for human CYP2D6. This isoform was selected because of its broad substrate promiscuity and high importance in drug metabolism.
We have tested inexpensive chemicals to replace the natural cofactors of CYP2D6, NADPH and cytochrome P450 reductase (CPR). The results showed that cumene hydroperoxide and tert-butyl hydroperoxide can successfully substitute CPR and NAD(P)H with retained regio- and stereo-selectivity. Moreover, with these surrogates, product formation and initial rates are increased by as much as two fold compared to the use of the natural cofactors.
It is widely accepted that even small proportions of organic solvents in the buffer can deactivate most enzymes including P450s. Our studies on the biocatalysis of CYP2D6 in organic solvent/buffer emulsions showed that under the optimized conditions, as much as 76% of the enzyme activity was retained. Product formation in biphasic solvent systems is comparable whether the natural redox partner and cofactor are used, or a surrogate. In addition, a correlation was observed between the log P and the suitability of a solvent for enzymatic activity, with higher log P resulting in higher enzymatic activity. These results were obtained with dextromethorphan (DXM), a water soluble substrate. A very hydrophobic substrate, 7-benzyloxy-4-N,N-diethylaminomethyl-coumarin (BDAC), was also tested successfully to demonstrate the utility of this method.
Lyophilization is usually required to remove water before using enzymes in nearly anhydrous solvents. This physical process is harmful to P450 enzyme activity. We therefore tested numerous sugars as lyoprotectant during lyophilization. Addition of trehalose or sucrose before lyophilization allowed the retention of 80% of the CYP2D6 activity, compared to 40% remaining activity in its absence. CYP2D6 co-lyophilized with trehalose was next tested in selected hydrophobic organic solvents in the absence of water. The enzymatic activity was found to strongly depend on the hydrophobicity of the solvent. Interestingly, the enzyme showed higher catalytic ability in n-decane or n-dodecane than in the standard buffer. This was unexpected considering that the activity of most enzymes was reported to decrease to 10% or less in nearly anhydrous organic solvents.
The last objective of this thesis was to improve the stability and/or activity of CYP2D6. Use of DNA self-assemblies to encapsulate P450 enzymes was envisaged to potentially increase their stability. Indeed, DNA assemblies have many advantages compared to traditional solid supports reported for enzymes. Our preliminary results showed that CYP2D6 templated the formation of cyclic DNA dimeric and tetrameric over polymeric self-assemblies. Characterization of the CYP2D6 activity in the presence of the DNA self-assemblies revealed no loss of activity or stability.

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7

Rodrigues, N. R. "The human cytochrome P-450 21-hydroxylase genes." Thesis, University of Oxford, 1987. http://ora.ox.ac.uk/objects/uuid:77be8950-4675-4a55-ab4f-27b788082007.

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Deficiency of the cytochrome P-450 steroid 21-hydroxylase (21-OHase) which causes Congenital Adrenal Hyperplasia (CAH) is a monogenic autosomal recessive disorder which is linked to HLA. There are two 21-OHase genes in man, A and B, and they are mapped to the HLA class III region ~ 3 kb 3' to the complement genes C4A and C4B, respectively. Two genes encoding 21-OHase were isolated, characterized and sequenced. Both 21-OHase genes are ~ 3.3 kb in length and are split into 10 exons by nine introns. Comparison of the two genes showed that although they are highly conserved, there are three deleterious mutations in the 21-OHase A gene which cause frameshifts and introduce in phase premature termination codons. Thus the 21-OHase A gene is a pseudogene. Comparison of the 21-OHase B gene to the other cytochrome P-450 sequences revealed that although the cysteine-429 was conserved in 21-OHase, there is very little homology with other cytochrome P-450, indicating it belongs to a separate family of genes within the superfamily. Clear evidence of polymorphism in 21-OHase is apparent on comparison with other 21-OHase B sequences. There is a size polymorphism of 494 and 495 amino acids. The differing severities of 21-OHase deficiency in CAH may be due to allelic variants of the 21-OHase B gene, since in most cases the defect is not due to gene deletion (Rumsby et al., 1986). A 21-OHase B gene from a patient with CAH was characterized and sequenced. There were 13 nucleotide alterations in his single 21-OHase B gene, one of which at codon 269 caused a serine to change to a threonine residue. The G → C transversion in the 21-OHase B gene from the patient at codon 269 introduced a new NcoI restriction site into the gene. This restriction fragment length polymorphism (RFLP) was used to study other patients with CAH and normal individuals. The NcoI RFLP was found not to be confined to the 21-OHase B gene but was also present in some 21-OHase A genes. It is likely therefore that the mutation occurred in the pseudogene first and then transferred to some 21-OHase B genes.

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8

Slatcher, Guy. "The mechanistic enzymology of cytochrome P-450 aromatase." Thesis, University of Southampton, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307085.

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9

Chow, Cathy Sze-Yu. "Selective hydroxylations catalysed by cytochrome P-450 monooxygenases." Thesis, University of Edinburgh, 1998. http://hdl.handle.net/1842/13386.

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The biohydroxylation potential of the mutant enzyme, cytochrome P-450 cam Y96A monooxygenase (Y96A), has been investigated with a series of substrates which differ structurally from that of the natural substrate, D-(+)-camphor. Design of substrates essentially consisted of coupling an aromatic side-chain with an alicyclic moiety via an ester, ether or amide link. Assays have been performed with Y96A in order to obtain data on key factors of the biohydroxylation reaction such as substrate binding and turnover to give hydroxylated products. Y96A research has been complemented by a thorough investigation of the biohydroxylation capability of bacterium, Rhodococcus rhodochrous NCIMB 9703. Compounds found to be inactive with Y96A were reacted with this whole cell system, and positive results have been achieved in all cases.

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10

Hawkes, David B. "Cytochrome P450cin /." St. Lucia, Qld, 2003. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17457.pdf.

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11

Gooden, Kyna McCullough Schroeder Jane C. "The relationship of uterine leiomyomata and genetic polymorphisms of Cytochrome P-450 1A1, Cytochrome P-450 1B1, and Catechol-O-Methyltransferase." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2006. http://dc.lib.unc.edu/u?/etd,303.

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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2006.
Title from electronic title page (viewed Oct. 10, 2007). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Epidemiology, School of Public Health." Discipline: Epidemiology; Department/School: Public Health.

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12

Hansen, Antony James. "Regulation of the expression of phenobarbital-inducible P450 genes." Title page, contents and summary only, 1989. http://web4.library.adelaide.edu.au/theses/09PH/09phh2491.pdf.

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13

Bell, Stephen Graham. "The use of active site mutants of cytochrome P450(cam) in chemical synthesis." Thesis, University of Oxford, 1999. http://ora.ox.ac.uk/objects/uuid:7f48cf79-37b0-45cd-a40e-e971af466cff.

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This thesis describes a study of the substrate selectivity of active site mutants of the monooxygenase cytochrome P450_cam. A range of mutants was constructed which replaced the phenolic side-chain at the Tyr-96 position by various hydrophobic amino acid residues. These 'hydrophobic mutants' were then combined with other mutations around the active site (Val-247, Phe-87, Ile-395 and Phe-193) which altered the space available at different positions in the active site. These mutants were then tested with an in vitro reconstituted P450_cam system with a range of substrates related to diphenylmethane and phenylcylcohexane. All of these large compounds were poor substrates for the wild-type enzyme. It was found that it was necessary to increase both the space available in the active site and the active site hydrophobicity to achieve substrate turnover. The substrates were oxidised preferentially on the aliphatic cyclohexyl ring over the more constrained phenyl ring suggesting that the active site is predisposed to binding the cyclohexyl ring close to the haem. Hydroxylation using the in vitro reconstituted P450_cam system is limited by catalyst lifetime and the need for the expensive cofactor NADH. For P450_cam hydroxylation to become a viable synthetic method it is necessary to find ways to bypass the use of NADH. For this reason various self-sufficient P450_cam system were constructed and expressed in E. coli. The best of these, despite limited protein expression, was found to turnover camphor with the wild-type P450_cam enzyme and other substrates with the Y96A mutant. The in vivo catalytic system was then used to screen many P450_cam mutants for the oxidation of natural products, monoterpenes and sesquiterpenes (e.g. limonene, pinene and valencene). Most of the target substrates are not oxidised by the wild-type enzyme but all are hydroxylated by some if not all of the P450_cam mutants with different degrees of selectivity. Some of the products identified so far are important compounds in the field of flavour and fragrance chemistry (e.g. verbenol and nookatone).

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14

Keck-Oertle, Maja. "Heterogeneity of cytochrome P-450 : biochemical and biophysical studies /." [S.l.] : [s.n.], 1986. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=8007.

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15

Cottrell, S. "Studies on cytochrome P-450 in some higher plants." Thesis, University of Surrey, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.377985.

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16

Makowski, Ryszard Jan Zygmunt. "Induction and characterisation of cytochrome P-450 multiple forms." Thesis, University of Surrey, 1985. http://epubs.surrey.ac.uk/844027/.

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The isolation and purification of two major phenobarbitone-induced hepatic cytochromes P-450 from male Wistar rats is described. These forms (designated cytochromes P-450 B1 and P-450 B2) were extensively characterised and structurally and functionally compared to two other homogeneous isoenzymic forms, cytochromes P-452 (clofibrate-induced) and cytochrome P-447 (BNF-induced). These characterisation studies (including catalytic, immunological, physical and spectral analysis) indicated that all four isoenzymes were distinct, unique hemoproteins. The above characterisation was extended towards the induction profiles of these hemoproteins in hepatic and renal microsomes, following single dose xenobiotic pretreatment. Of primary interest was the immunoquantitation data which revealed the presence of cytochrome P-452 as a major constitutive isoenzyme. This data in conjunction with the metabolic data also indicated that xenobiotic induction of cytochromes P-450 was both a specific and precise event. In order to determine the induction profile of these hemoproteins following xenobiotic pretreatment, analysis of the mRNA species was also undertaken. In vitro rabbit reticulocyte translation systems in conjunction with immunoprecipitation analysis (using monospecific antibodies against the specific cytochrome P-450) revealed that following phenobarbitone and beta-napthoflavone pretreatment the induction of the specific translatable mRNA species was due to a difference in the amount of specific mRNA and not to a change in its translatability. This induction profile corresponded to that found on analysis of the holoenzyme cytochromes P-450 present within hepatic microsomes. The temporal aspects of the induction of the mRNA species coding for cytochrome P-452 was not in agreement with the metabolic and immunochemical data for this isoenzyme in hepatic microsomes. This discrepancy is possibly believed to relate to the activation/repression of genes coding for similar and related cytochrome P-452 isoenzymes. A preliminary analysis of renal mRNA species coding for the cytochromes P-450 in conjunction with metabolic data was strongly suggestive for there being different modes of induction in the liver and kidney.

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17

Gartner, Carlos A. "Human cytochrome P-450 aromatase : purification and structural studies /." Thesis, Connect to this title online; UW restricted, 2001. http://hdl.handle.net/1773/8183.

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18

Wennerholm, Agneta. "Characteristics of cytochrome P450-catalysed drug metabolism with focus on a black Tanzanian population /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-697-9/.

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19

Rosic, Nedeljka. "Molecular breeding of cytochrome P450s for indigoid pigment production /." [St. Lucia, Qld.], 2005. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18978.pdf.

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20

Stok, Jeanette Elizabeth. "Biosynthetic cytochrome P450s /." [St. Lucia, Qld.], 2001. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16210.pdf.

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21

Dickmann, Leslie J. "Characterization of CYP2C9 residues important for conferring substrate specificity and inter-individual variability in drug metabolism /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/8184.

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22

Henne, Kirk R. "The active site characteristics of the cytochrome P450 4B1 bioactivation enzyme /." Thesis, Connect to this title online; UW restricted, 2001. http://hdl.handle.net/1773/8159.

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23

Elferink, Lisa Anne. "Characterization of the chicken phenobarbital inducible P450 gene family /." Title page, contents and introduction only, 1987. http://web4.library.adelaide.edu.au/theses/09PH/09phe39.pdf.

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24

Rodrigues, Amilcar David. "The interactions of imidazole drugs with cytochromes P-450." Thesis, University of Surrey, 1988. http://epubs.surrey.ac.uk/847959/.

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The major forms of cytochrome P-450 protein induced by phenobarbital (P-450[b]) and 3-methylcholanthrene (P-450[c]) have been isolated, purified to electrophoretic homogeneity and fully characterised with respect to substrate specificity. The purified cytochrome P-450[c] was used as antigen in the preparation of sheep polyclonal antibodies, which were used for the immunological detection, characterisation and quantification of the haemoprotein. The N1-substituted antifungal agents, ketoconazole, miconazole and clotrimazole, have been shown to be potent in vitro inhibitors of both the phenobarbital-induced cytochrome P-450- and the 3-methylcholanthrene-induced cytochrome P-448-dependent rat hepatic mixed-function oxidases. All three drugs were more potent inhibitors of the phenobarbital-induced activities in microsomal systems, as well as in reconstituted systems comprising purified NADPH-cytochrome P-450 reductase and cytochrome P-450[b] or P-450[c]. Ketoconazole was the weakest inhibitor and the least selective for the former haemoprotein. All three antimycotic agents elicited type II difference spectra with microsomes from both phenobarbital- and 3-methylcholanthrene-induced rats, as well as with both purified haemoprotein preparations. Miconazole and clotrimazole, and to a lesser extent ketoconazole, have been shown to decrease the magnitude of the type I spectral perturbation of hexobarbital with phenobarbital-induced microsomes. These observations indicate that, although the primary mechanism of inhibition involves reversible binding to haem, an additional interaction with the apoprotein or substrate (type I) binding site is involved and may contribute to the isoenzyme selectivity displayed by all three compounds. When administered systemically to rats, all three antifungal agents stimulated the hepatic microsomal mixed-function oxidases, particularly those activities associated with the phenobarbital and/or pregnenolone-16a-carbonitrile-induced cytochromes P-450. This was confirmed by Western blotting employing anti-cytochrome P-450[p] (PB[2C]) and anti-cytochrome P-450[b]. Administration of the planar benzimidazole 2-amino-3-methylimidazo-(4,5-f)-quinoline (IQ), a food mutagen and carcinogen, in contrast to the globular antifungal agents, selectively induced the cytochromes P-448, especially the high spin form (cytochrome P-450[d]).

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25

Davidson, Benjamin Paul. "Studies on the regulation of the barbiturate-inducible cytochrome P450 genes CYP2H1 and CYP2H2 : a thesis submitted for the degree of Doctor of Philosophy at the University of Adelaide." Title page, contents and abstract only, 2000. http://web4.library.adelaide.edu.au/theses/09PH/09phd252.pdf.

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26

Koenigs, Luke L. "Mechanism-based inactivation of P450 /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/8150.

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27

Plante, Mélanie. "Étude biophysique du Cytochrome P4503A4 humain." Thesis, Université Laval, 2007. http://www.theses.ulaval.ca/2007/24323/24323.pdf.

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28

Tyzack, Jonathan David. "Prediction of cytochrome P450 xenobiotic metabolism." Thesis, University of Cambridge, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708289.

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29

Stanley, Lesley A. "Cytochrome P-450 regulation in human tumour-derived cell lines." Thesis, University of Edinburgh, 1992. http://hdl.handle.net/1842/26969.

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Cytochrome P-450s (P-450s) comprise a polymorphic multigene family of haem-containing enzymes which are essential to the Phase I metabolism of xenobiotics. They take part in activation and detoxification of carcinogens and anticancer drugs; thus an understanding of these enzymes is essential to the prevention and treatment of cancer. Induction of P-450s by drugs and carcinogens has been extensively studied; endogenous regulation of P-450s also occurs during normal development and disease. The aim of this project was to develop an in vitro system in which to study P-450 induction and modulation during inflammation. P-450 regulation in five human tumour-derived cell lines, HepG2 (liver) NCI H322, NCI H358 (lung), HT29 and LS174T (colon) was examined. The liver cell line was chosen because of this organ's importance in xenobiotic metabolism and the known effects of inflammation on hepatic P-450 expression; the lung and colon lines were selected because these organs also express P-450s and are subject to inflammatory disorders which may be involved in tumorigenesis. The cell lines expressed variable levels of 7-ethoxyresorufin O-deethylase (EROD) which could be induced by benzanthracene (BA); after BA treatment isozyme MC_1b could be detected by Western blot analysis. The lung cell line NCI H322 was selected for further study. Induction of isozyme MC_1b in this cell line involved an increase in steady-state mRNA expression; further experiments established suitable conditions for induction (5μg/ml BA in RPMI medium containing 10% foetal calf serum). The MTT assay was used to estimate the toxicity of P-450 inducers towards HEPG2 and NCI H322 cells and to examine the effects of P-450 induction on the toxicity of benzo(a)pyrene (B(a)P) and cyclophosphamide.

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30

Schöneboom, Jan Claasen Curd. "Combined quantum mechanical - molecular mechanical calculations on cytochrome P450cam." [S.l. : s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=968865267.

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31

Regal, Kelly Anne. "Caffeine as an active site probe of cytochrome P4501A2 /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/8168.

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32

Bhatia, Deepak. "Characterization of CYP2D protein from human brain cerebellum." Morgantown, W. Va. : [West Virginia University Libraries], 2004. https://etd.wvu.edu/etd/controller.jsp?moduleName=documentdata&jsp%5FetdId=3730.

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Thesis (M.S.)--West Virginia University, 2004
Title from document title page. Document formatted into pages; contains ix, 49 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 41-48).

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33

Hu, Yin. "Genetic polymorphism and regulation of cytochrome P450 2E1 /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3690-0.

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34

Wen, Bo. "Analysis of human CYP3A4 structure-function relationships using photoaffinity labels /." Thesis, Connect to this title online; UW restricted, 2005. http://hdl.handle.net/1773/8154.

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35

Roh, Hyung-Keun. "Drug metabolic capacity in Koreans : CYP2D6 & CYP2C19 pheno- and genotype relationships in healthy volunteers and in patients /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-169-1.

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36

Ayscue, Robyn Renee. "Computer modeling of dapsone-mediated heteroactivation of flurbiprofen metabolism by CYP2C9." Morgantown, W. Va. : [West Virginia University Libraries], 2008. https://eidr.wvu.edu/etd/documentdata.eTD?documentid=5642.

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Thesis (Ph. D.)--West Virginia University, 2008.
Title from document title page. Document formatted into pages; contains viii, 174 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 164-174).

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37

Parker, G. L. "Induction of cytochrome P-450 in in vitro hepatocyte culture systems." Thesis, University of Surrey, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.370713.

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38

Reed, C. J. "Studies of cytochrome P-450-dependent reactions in the olfactory epithelium." Thesis, University of Cambridge, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.374871.

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39

Freeman, Jonathan Edward. "The role and regulation of the cytochrome P-450 CYP2E subfamily." Thesis, University of Edinburgh, 1993. http://hdl.handle.net/1842/19766.

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Several cytochrome P-450 enzymes are thought to have evolved to metabolise lipophillic xenobiotics allowing subsequent conjugatory and excretory steps to occur. The nature of the metabolic activity of these enzymes and their ability to activate a series of carcinogens has implicated them in carcinogenesis. The CYP2E subfamily activates a series of common carcinogens including N-nitrosodimethylamine (NDMA); situations therefore in which CYP2E levels are elevated may lead to increased carcinogenic risk. A mouse CYP2E cDNA and the single copy CYP2E gene were cloned and characterised and the regulation of CYP2E in this species was studied. Mouse CYP2E protein levels were seen to be elevated by acetone in a variety of tissues; no concomitant increase in CYP2E mRNA was seen. Previous studies in the rat suggested that the CYP2E elevation resulted from substrate induced protein stabilisation. This stabilisation was suggested to be mediated by the presence of the substrate leading to the blocking of a phosphorylation event which may trigger CYP2E protein degradation. This was investigated using mutant forms of the mouse CYP2E protein lacking the phosphorylation site; in mammalian tissue culture systems both mutant and native CYP2E proteins behaved identically suggesting that the protein stabilisational event may be mediated via a mechanism other than the blocking of a phosphorylational change in the CYP2E protein. The CYP2E mRNA and protein became elevated both in the spontaneously diabetic BB/E rat, and the mouse following starvation. As a result of increased β-oxidation in these states ketone body levels become elevated which may lead to stabilisation of the CYP2E protein. Previous studies in chemically induced diabetic rats suggested that the message elevation resulted from the stabilisation of pre-existing CYP2E transcripts; previously characterised events of this kind were seen to be mediated by elements within the 3' untranslated region (UTR) of a message.

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Liu, Luo. "Cloning, expression, characterization and engineering of cytochrome P450 CYP116B3 from Rhodococcus ruber DSM 44319." [S.l. : s.n.], 2007. http://nbn-resolving.de/urn:nbn:de:bsz:93-opus-34315.

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41

Herrlin, Karin. "CYP2C19 catalyzed drug metabolism in different populations /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4786-4/.

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42

Schrag, Michael L. "Development of active site directed probes for cytochrome P450 /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/8153.

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43

Beck, Nancy Beth. "Phenobarbital mediated induction of the cytochrome P450 2B genes : mechanistic investigations /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/8449.

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Trnka, Michael J. "Photoaffinity labeling of cytochrome P450s with imidazole-tethered benzophenone compounds /." Thesis, Connect to this title online; UW restricted, 2004. http://hdl.handle.net/1773/8516.

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Nordmark, Anna. "Functional features of human cytochrome P450 1A2 with special focus on caffeine and melatonin metabolism /." Stockholm : [Karolinska institutets bibl.], 2002. http://diss.kib.ki.se/2002/91-7349-364-3/.

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46

Upthagrove, Alana L. "CYP2D6 and CYP1A2 catalyzed metabolism of propranolol related fluorinated amines : effects of changes in amine pKa and other properties /." Thesis, Connect to this title online; UW restricted, 2001. http://hdl.handle.net/1773/8167.

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47

McConn, Donavon J. "Metabolic and inhibitory differences between cytochromes P450 3A4 and 3A5 /." Thesis, Connect to this title online; UW restricted, 2001. http://hdl.handle.net/1773/7980.

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48

Ciaccio, Paul Joseph. "Structural and functional characterization of dog liver cytochromes P-450." Diss., The University of Arizona, 1989. http://hdl.handle.net/10150/184775.

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I. Chloramphenicol (CAP) is a potent and selective mechanism-based inactivator of the major phenobarbital (PB)-inducible form of dog liver cytochrome P-450 (PBD-2) in vitro. In a reconstituted system, CAP inactivates PBD-2 in a time- and NADPH-dependent manner and binds covalently to the protein moiety of PBD-2 with a stoichiometry of 1 nmol CAP bound/nmol P-450 inactivated. In intact liver microsomes from PB-treated male Beagle dogs, CAP irreversibly inhibits androstenedione 16α- and 16β-hydroxylation and 2,4,5, 2',4',5'-hexachlorobiphenyl hydroxylation but not androstenedione 6 β -hydroxylation or NADPH-dependent triacetyloleandomycin (TAO) complex formation. Covalent binding of CAP to dog liver microsomes in vitro is increased 5.5-fold by PB induction. This increase correlates well with the increased levels of immunochemically determined PBD-2 (5.8-fold) and 16α - and 16β -hydroxylation of androstenedione (5.7- and 5.8-fold) in microsomes from PB-treated dogs. Anti-PBD-2 IgG significantly inhibits the covalent binding of CAP to microsomes from untreated and PB-treated dogs. Finally, CAP appears to bind covalently with a single protein with the same molecular weight as PBD-2, as evidenced by SDS-PAGE. II. A cytochrome P-450 called PBD-1 isolated from liver microsomes of an adult male Beagle dog treated with PB is structurally and functionally similar to members of the P450IIIA gene subfamily in rat and human liver microsomes. The sequence of the first 28 amino terminal residues of PBD-1 is identical in 15 and 20 positions, respectively, to the P450IIIA forms P450p from rat and P450(NF) from human. Upon immunoblot analysis, anti-PBD-1 IgG recognizes PCNa (P450p) and PCNb (PB\PCN-E) from rat, P450(NF) from human, and two proteins in liver microsomes from untreated and PB-treated dogs. Anti-PBD-1 IgG selectively inhibits P450IIIA form marker activities, including steroid 6β -hydroxylase, erythromycin demethylase and NADPH-dependent TAO complex formation in microsomes from PB-treated dogs. Major species differences exist in the apparent K(m) for 6β -hydroxylation of androstenedione by liver microsomes from humans, untreated rats and untreated dogs. In addition, evidence for functional heterogeneity of dog P450IIIA forms is presented: pretreatment of microsomes from PB-treated dogs with TAO plus NADPH had no effect on androstenedione 6β -hydroxylase activity.

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Zukunft, Jörg. "Functional characterization of promoter polymorphisms in the human Cytochrome P450 2B6 gene (CYP2B6)." [S.l. : s.n.], 2005. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB11947836.

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50

Rylander, Rudqvist Tove. "Extrahepatic cytochrome P450s : relation to cancer susceptibility /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-601-4/.

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