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
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OKQ.1974/5321 |
| Date | 18 November 2009 |
| Creators | Hum, MAAIKE |
| Contributors | Queen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.)) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English, English |
| Detected Language | English |
| Type | Thesis |
| Format | 5841081 bytes, application/pdf |
| Rights | This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner. |
| Relation | Canadian theses |
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