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Thesis (M.S.)--University of Michigan, 1975. / Typescript (photocopy). Includes bibliographical references (leaves 40-49). Also issued in print.

Thesis (M.S.)--University of Michigan, 1975. / Typescript (photocopy). eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 40-49).

Thesis (doctoral)--Universität Hamburg, 1979.

The glucocorticoid receptor (GR) is a member of the nuclear hormone receptors family and has been shown to exert significant effects on the induction of cytochrome P450 (CYP) enzymes responsible for the metabolism of many xenobiotics. CYP3A4/5 and CYP2C9 are important CYP enzymes which metabolise more that 60% of drugs. Induction or inhibition of the enzymatic activity and the levels of these enzymes can have significant effects on drug metabolism. Understanding the role of GR and other nuclear receptors, pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), in the mechanisms effecting CYP3A4/5 and CYP2C9 levels and activity can aid in the development of in vitro and in vivo models which have become a target for scientists in the clinic and the industry. The commonly prescribed synthetic glucocorticoid (GC) drug, dexamethasone (Dex), can induce GR, PXR and CAR and was used in this study to analyse its effects on the CYP enzymes studied. The hypothesis of this project was that changes in CYP3A4/5 and CYP2C9 gene expression affect drug metabolism and changes in gene expression of these CYP enzymes was under GR, PXR and CAR control, thus affecting the concentration and therapeutic activity of drugs metabolized by these enzymes during chronic use of GCs in conditions such as rheumatoid arthritis and asthma. This study aimed to measure mRNA, protein, ROS and enzymatic activity levels in human HepG2 hepatocytes treated with Dex for 120 h and analyze the results for various time points to produce a mathematical model. Our study has shown that changes in mRNA, protein and enzymatic activity levels of CYP3A4/5 and CYP2C9 in HepG2 cells were induced by Dex at sub-micromolar (0.1 µM) and supra-micromolar (1.5 mM) concentrations. The induction of CYP3A4/5 and CYP2C9 enzymes during 120 h treatment with Dex may be affected by the NRs studied; GR, phosphorylated GR, PXR and CAR protein levels were also shown to be induced by Dex. The efflux transporter, P-gp’s protein levels were also induced by 0.1 µM Dex, highlighting the importance of considering bioavailability of other drugs co-administered with Dex. The results of some of these laboratory experiments have been used to produce mechanistic mathematical models by MATLAB software with reference to previous studies in rats concentrating on the effects of steroids on GR. The models developed were not effective at the lower Dex concentration of 0.1 µM but were better modelled at the higher Dex concentration of 1.5 mM. The basic mechanistic models developed using HepG2 cells in this study can be utilised to design and conduct drug-drug interaction (DDI) analyses of the induction of CYP3A4/5 and CYP2C9 in other human liver cells and starting pre-clinical studies in animals to aid in drug development.

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Glucocorticoids are widely used in horses for a variety of autoimmune and inflammatory conditions. Its potent antiinflammatory properties have been associated with the suppression of a number of different inflammatory cytokines. The purpose of the study was to evaluate the effect of dexamethasone treatment in horses on mRNA cytokine expression, including interleukin-1Î , interferon-gamma, interleukin-4 and interleukin-6, during a five day treatment period and a five day post treatment period. A randomized complete block design was performed on 16 healthy horses. Group I (8 horses) received 0.1 mg/kg of dexamethasone sodium phosphate by intravenous injection once daily for 5 days. Group II (8 horses) received an equivalent volume of sterile saline by intravenous injection daily for 5 days. A sample of 5x10 mililiters of blood in acid citrate dextrose was obtained prior to initial treatment. Thirty minutes after each treatment injection (placebo or dexamethasone) a sample of blood was obtained during the 5 day treatment period and 24, 48, 72, 96 and 120 hours after the last treatment injection was administered. Peripheral-blood mononuclear cells were isolated from the blood samples and stimulated with concavalin A. RNA was isolated using the QIAGEN RNeasy kit. cDNA first strand synthesis was achieved using QIAGEN's OMMISCRIPT RT KIT. cDNA was also constructed for the house keeping gene Î actin. Primer pairs specific for each cytokine were designed using equine cytokine sequences available on Genbank. cDNA for each cytokine and Î -actin was amplified using Real Time PCR technique. Interleukin-4, interleukin-6 and interferon-gamma mRNA expression was statistically significant suppressed in horses treated with dexamethasone when compared to control horses. Interleukin-1Î was only significantly suppressed on day 5. Interleukin-4, interleukin-6 and interferon-gamma mRNA expression suppression was initially observed on day 2 and lasted 24 hours after the last dose of dexamethasone was administered. Interleukin-6 mRNA expression was significantly higher when compared to control group on day 10. Our results suggest that dexamethasone treatment of healthy horses suppresses mRNA expression of several cytokines, including interleukin-4, interleukin-6 and interferon-gamma. This effect could explain part of corticosteroid's mechanism of action for controlling inflammation in a variety of disease conditions. The time-course effect of dexamethasone showed that the effect on mRNA cytokine expression suppression is only observed on day 2 of treatment and mRNA suppression is maintained for 24 hours after discontinuation of treatment. / Master of Science

Thesis (Ph.D.)--University of Florida, 2004. / Typescript. Title from title page of source document. Document formatted into pages; contains 139 pages. Includes Vita. Includes bibliographical references.

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