Analytical and metabolic studies of Mitotane and its analogues.
dc.contributor.author | Ruangwises, Nongluck | en_US |
dc.contributor.advisor | Sinsheimer, Joseph E. | en_US |
dc.date.accessioned | 2014-02-24T16:28:44Z | |
dc.date.available | 2014-02-24T16:28:44Z | |
dc.date.issued | 1990 | en_US |
dc.identifier.other | (UMI)AAI9023629 | en_US |
dc.identifier.uri | http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:9023629 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/105556 | |
dc.description.abstract | Mitotane ($o,p\sp\prime$-DDD; 2,2 bis(2-chlorophenyl-4-chlorophenyl)-1,1-dichloroethane) has been used in the treatment of adrenal neoplasms and benign Cushing's syndrome. The use of Mitotane is limited by its toxicity. In an attempt to develop possible improved agents, Mitometh, a methyl derivative of Mitotane, and unsaturated Mitometh, a major impurity in Mitometh, were studied. Neither of them showed adrenolytic activity in dogs. Analytical chemical techniques were developed and applied to compare the adrenolytic activity of Mitotane, Mitometh and unsaturated Mitometh and to study the effectiveness of Mitotane in patients. Mitochondrial and especially the cytosolic fractions were found to have the highest activity in transformations of DDD in the adrenal. The microsomal fraction showed the highest activity and the mitochondrial and cytosolic fractions showed negligible activity in the liver. $\alpha$-Hydroxy DDD was found to be a major metabolite in $p,p\sp\prime$-DDD but not $o,p\sp\prime$-DDD transformations, in adrenals. Studies on the characterization of the adrenal cytosolic fraction responsible for Mitotane and $p,p\sp\prime$-DDD transformations were initiated. The activity in this fraction required oxygen but not glutathione and could be inhibited by ketoconazole, a P-450 inhibitor. However, a typical carbon monoxide curve could not be detected in this fraction and P-450$\sb{\rm scc}$ content of the fraction, detected by gel electrophoresis and immunoblotting, was only one tenth of that obtained from adrenal mitochondria although adrenal cytosol had 8 times more cholesterol side-chain cleavage activity than in the mitochondria. | en_US |
dc.format.extent | 122 p. | en_US |
dc.subject | Health Sciences, Pharmacology | en_US |
dc.subject | Health Sciences, Pharmacy | en_US |
dc.title | Analytical and metabolic studies of Mitotane and its analogues. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Pharmaceutical Chemistry | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/105556/1/9023629.pdf | |
dc.description.filedescription | Description of 9023629.pdf : Restricted to UM users only. | en_US |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
Files in this item
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.