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The effects of small molecule heme oxygenase inhibitors on rat cytochromes P450 2E1 and 3A1/2Hum, MAAIKE 18 November 2009 (has links)
Heme oxygenases (HO) catalyze the degradation of heme into biliverdin, carbon monoxide (CO) and free iron. The two major isoforms, HO-2 (constitutive) and HO-1 (inducible by various stressors such as heavy metals and reactive oxygen species) are involved in a variety of physiological functions, including anti-inflammation, antiapoptosis, neuromodulation, and vascular regulation. Major tools used in exploring these actions have been metalloporphyrin analogs of heme that inhibit the HOs. However, these tools are limited by their lack of selectivity; they affect other heme-dependent enzymes, such as cytochromes P450 (CYPs), soluble guanylyl cyclase (sGC), and nitric oxide synthase (NOS). Our laboratory has been able to successfully synthesize a series of small molecule non-porphyrin HO inhibitors (QC-xx) that have had little or no effect against sGC and NOS; however, their effects on various CYP isoforms has yet to be fully elucidated. In order to determine the effects on CYP enzyme activity, microsomal preparations of two CYP isoforms (2E1 and 3A1/3A2) were incubated with varying concentrations of HO inhibitor and the activity was determined via spectrophotometric analysis. Results indicated that some QC compounds demonstrated little to no inhibition of CYP2E1 and/or CYP3A1/2, while some others did inhibit these CYP isoforms. Four regions of interest were analyzed further and several structural changes were identified as conferring increased HO inhibition and decreased effect on both CYP2E1 and 3A1/2. Based on the information obtained, three putative compounds were designed and it is hypothesized that these compounds will be selective inhibitors for HO-1 over HO-2 and will display little effect on either CYP2E1 or 3A1/2 activities. / Thesis (Master, Pharmacology & Toxicology) -- Queen's University, 2008-11-20 11:19:48.841
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Development of nanobiosensors for phenolic endocrine disrupting compounds and anti- tuberculosis drugsSidwaba, Unathi January 2013 (has links)
>Magister Scientiae - MSc / Tuberculosis still remains one of the world’s killer diseases. Pyrazinamide (PZA) is one of
the most commonly prescribed anti-tuberculosis (anti-TB) drugs due to its ability to
significantly shorten the TB treatment period. However, excess PZA in the body caused
hepatotoxicity and liver damage. This, together with the resistance of the bacteria to
treatment drugs, poor medication and inappropriate dosing, contribute significantly to the high incidents of TB deaths and diseases (such as liver damage). This, therefore, calls for new methods for ensuring reliable dosing of the drug, which will differ from person to person due to inter-individual differences in drug metabolism. A novel biosensor system for monitoring the metabolism of PZA was prepared with a nanocomposite of multi-walled carbon nanotubes (MWCNTs), polyaniline (PANI) and cytochrome P450 2E1 (CYP2E1) electrochemically deposited on a glassy carbon electrode (GCE). The nanocomposite biosensor system exhibited enhanced electro-activity that is attributed to the catalytic effect of the incorporated MWCNTs. The biosensor had a sensitivity of 7.80 μA/ μg mL-1 PZA and a dynamic linear range (DLR) of 4.92 – 160 ng/mL PZA. Bisphenol A (BPA) is a hormone-disrupting chemical used in production of epoxy resins and polycarbonates, which produce various products used on a daily basis. However, BPA can leach out of plastic during normal use and cause health effects such as cancer or disrupt the endocrine system. Moreover, BPA has also been proven to degrade from the containers in landfills and accumulate in groundwater and streams, thereby, polluting the environment while destroying aquatic organisms. Therefore, this also calls for new selective and sensitive methods for the monitoring of BPA. A novel biosensor system for monitoring the oxidation of BPA was prepared from a nanocomposite of polyaniline, polymethyl methacrylate and titanium dioxide nanoparticles, also electrochemically deposited on the GCE. Biosensor fabrication was conducted by immobilization of the enzyme manganese peroxidase (MnP)
iii onto the nanocomposite film. The nanobiosensor also revealed enhanced electro activity, attributed to the incorporation of TiO2 nanoparticles. The biosensor system had a sensitivity of 0.3 μA/nM and a detection limit of 0.12 nM. This detection limit falls within the range of the allowed daily intake of BPA as recommended by the Food and Drug Administration (FDA, USA) and other regulatory bodies.
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Nanoparticulate of silver-modified poly (8-anilino-1-naphthalene sulphonic acid) nanobiosensor systems for the determination of Tuberculosis treatment drugsNgece, Rachel Fanelwa. January 2011 (has links)
This study firstly reports the development and characterization of PVP-AgNPs, PANSA and PVPAgNPs/ PANSA nanocomposite on gold. AFM and TEM analyses revealed highly electroactive nanocomposites whose morphogy and properties were essential for the immobilization of CYP2E1. Secondly, the development and characterization of Au/PVPAgNPs/ PANSA/CYP2E1, Au/PVP-AgNPs/PANSA/SA-CYP2E1 and Au/PVPAgNPs/ PANSA/EG-CYP2E1 nanobiosensors are reported. AFM studies displayed globular morphologies with large roughness for the enzyme modified electrodes as opposed to those electrodes without enzymes. Finally, the biotransformation of standard solutions of TB drugs (isoniazid, ethambutol, pyrazinamide and rifampicin) in pH 7.4, 0.1 M phosphate buffer solution is reported. The biotransformations of the TB drugs were successfully studied using cyclic voltammetry (CV), square wave voltammetry (SWV), differential voltammetry (DPV) and steady state amperometry under aerobic conditions. Very good detection limits were obtained for the standard solutions of TB drugs and were found to be in the micromolar range. The detection limit values for the individual TB drugs were 0.55 μM (isoniazid), 0.7 μM (ethambutol), 0.054 μM (pyrazinamide) and 0.05 μM (rifampicin). The detection limit results showed that the nanobiosensors were more sensitive and suitable for the determination of the respective drugs in plasma and serum.
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Nanoparticulate of silver-modified poly (8-anilino-1-naphthalene sulphonic acid) nanobiosensor systems for the determination of Tuberculosis treatment drugsNgece, Rachel Fanelwa. January 2011 (has links)
This study firstly reports the development and characterization of PVP-AgNPs, PANSA and PVPAgNPs/ PANSA nanocomposite on gold. AFM and TEM analyses revealed highly electroactive nanocomposites whose morphogy and properties were essential for the immobilization of CYP2E1. Secondly, the development and characterization of Au/PVPAgNPs/ PANSA/CYP2E1, Au/PVP-AgNPs/PANSA/SA-CYP2E1 and Au/PVPAgNPs/ PANSA/EG-CYP2E1 nanobiosensors are reported. AFM studies displayed globular morphologies with large roughness for the enzyme modified electrodes as opposed to those electrodes without enzymes. Finally, the biotransformation of standard solutions of TB drugs (isoniazid, ethambutol, pyrazinamide and rifampicin) in pH 7.4, 0.1 M phosphate buffer solution is reported. The biotransformations of the TB drugs were successfully studied using cyclic voltammetry (CV), square wave voltammetry (SWV), differential voltammetry (DPV) and steady state amperometry under aerobic conditions. Very good detection limits were obtained for the standard solutions of TB drugs and were found to be in the micromolar range. The detection limit values for the individual TB drugs were 0.55 μM (isoniazid), 0.7 μM (ethambutol), 0.054 μM (pyrazinamide) and 0.05 μM (rifampicin). The detection limit results showed that the nanobiosensors were more sensitive and suitable for the determination of the respective drugs in plasma and serum.
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Nanoparticulate of silver-modified poly (8-anilino-1-naphthalene sulphonic acid) nanobiosensor systems for the determination of Tuberculosis treatment drugsNgece, Rachel Fanelwa January 2011 (has links)
Philosophiae Doctor - PhD / This study firstly reports the development and characterization of PVP-AgNPs, PANSA and PVPAgNPs/ PANSA nanocomposite on gold. AFM and TEM analyses revealed highly electroactive nanocomposites whose morphogy and properties were essential for the immobilization of CYP2E1. Secondly, the development and characterization of Au/PVPAgNPs/ PANSA/CYP2E1, Au/PVP-AgNPs/PANSA/SA-CYP2E1 and Au/PVPAgNPs/ PANSA/EG-CYP2E1 nanobiosensors are reported. AFM studies displayed globular morphologies with large roughness for the enzyme modified electrodes as opposed to those electrodes without enzymes. Finally, the biotransformation of standard solutions of TB drugs (isoniazid, ethambutol, pyrazinamide and rifampicin) in pH 7.4, 0.1 M phosphate buffer solution is reported. The biotransformations of the TB drugs were successfully studied using cyclic voltammetry (CV), square wave voltammetry (SWV), differential voltammetry (DPV) and steady state amperometry under aerobic conditions. Very good detection limits were obtained for the standard solutions of TB drugs and were found to be in the micromolar range. The detection limit values for the individual TB drugs were 0.55 μM (isoniazid), 0.7 μM (ethambutol), 0.054 μM (pyrazinamide) and 0.05 μM (rifampicin). The detection limit results showed that the nanobiosensors were more sensitive and suitable for the determination of the respective drugs in plasma and serum. / South Africa
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Metallic nanoparticles with polymeric shell: A multifunctional platform for application to biosensorNgema, Xolani Terrance January 2018 (has links)
Philosophiae Doctor - PhD (Chemistry) / Tuberculosis (TB) is an airborne disease caused by Mycobacterium tuberculosis (MTB) that
usually affects the lungs leading to severe coughing, fever and chest pains. It was estimated
that over 9.6 million people worldwide developed TB and 1.5 million died from the infectious
disease of which 12 % were co-infected with human immunodeficiency virus (HIV) in the year
2015. In 2016 the statistics increased to a total of 1.7 million people reportedly died from TB
with an estimated 10.4 million new cases of TB diagnosed worldwide. The development of the
efficient point-of-care systems that are ultra-sensitive, cheap and readily available is essential
in order to address and control the spread of the tuberculosis (TB) disease and multidrugresistant
tuberculosis.
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