Adrenal proteins bound by a reactive intermediate of mitotane
Abstract
Purpose Mitotane (o,p'-DDD), is the only adrenolytic agent available for the treatment of adrenocortical carcinoma. Previous studies have shown that mitotane covalently binds to adrenal proteins following its metabolism in adrenocortical tissue to a reactive acyl chloride intermediate. It was the objective of this study to compare the electrophoresis separation patterns of such adducts following activation of mitotane by various adrenocortical sources.Methods With the use of a 125I-labeled analog of mitotane, 1-(2-chlorophenyl)-1-(4-iodophenyl)-2,2-dichloroethane, gel electrophoresis patterns were obtained for homogenates from bovine, canine and human adrenocortical preparations as well as from a human adrenal preparation. Western immunoblotting analysis was used to test the resulting patterns for adducts of cytochrome P-450scc and adrenodoxin.Results The electrophoresis separations were similar for all preparations, with bands at apparent molecular weights of 49.5 and 11.5 kDa being the most pronounced. Radiolabeling of the proteins of a human adrenal cancer cell line NCI H-295 was weak, but a band at 11.5 kDa was detected. Western immunoblotting analyses indicated that the band at 49.5 kDa corresponded in molecular weight to that of adrenal cytochrome P-450scc, but the band at 11.5 kDa did not correspond to adrenodoxin.Conclusions The similarity of the results with canine and bovine adrenal preparations to that of human material offers useful systems for studying mitotane and its analogs. This should aid in understanding the mechanism of action of mitotane and in the design of compounds for the treatment of adrenocortical carcinoma.
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Mitotane metabolites inhibit several enzymes in the adrenocortical steroidogenesis pathway, mainly CYP11A1 and CYP11B1.
“Furthermore, mitotane metabolites inhibit several enzymes in the adrenocortical steroidogenesis pathway, mainly at the level of the cholesterol side-chain cleavage enzymes CYP11A1 (which appears to be one of the covalently bound mitotane targets) and CYP11B1 (286, 287).”
From Adrenocortical carcinoma (2014) · cites this paper as [286]
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- Authors
- Cai, W., Counsell, R. E., Schteingart, D. E., Sinsheimer, J. E., Vaz, A. D. N., & Wotring, L. L.
- Affiliations
- University of Michigan (US)
- Venue
- Cancer Chemotherapy and Pharmacology
- Published
- 1997-02-28
- Volume
- 39
- Issue
- 6
- Pages
- 537-540
- ISSN
- 0344-5704 (ISSN-L)
- 1432-0843
- OpenAlex
- W2134450854
- Cited by
- 27
- References
- 24
- Citations by year
- 2025: 1 · 2024: 2 · 2022: 1 · 2021: 1 · 2020: 2 · 2018: 2 · 2017: 1 · 2016: 2 · 2014: 5 · 2013: 2
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cancer Chemotherapy and Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Deep Blue (University of Michigan) (acceptedVersion)
- Funders
- National Institutes of Health (5r01gm046807-03, 5r01ca037794-06)
- National Cancer Institute (R01 CA 37794, 2P30 CA 46512)
- National Institute of General Medical Sciences (GM 46807)
- Topics
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- mitotane, adrenocortical carcinoma, covalent binding, cytochrome P450scc, adrenodoxin, mechanism of action
- MeSH terms
- Adrenal Cortex, Animals, Autoradiography, Cattle, Cholesterol Side-Chain Cleavage Enzyme, Dogs, Humans, Mitotane, Protein Binding, Proteins, Blotting, Western, Antineoplastic Agents, Hormonal
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