Adrenal metabolism of mitotane and related compounds
Mitotane (o,p{prime}-DDD; 1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroethane) has been used in the treatment of Cushing's syndrome due to adrenal hyperfunction and it the drug of choice for adrenocortical carcinoma. The object of this investigation is to study the biotransformation of o,p{prime}-DDD and p,p{prime}-DDD in dogs and bovine adrenal cortex to explain its selective toxicity and mechanism of action. The in vitro biotransformation of {sup 14}C-labeled o,p{prime}-DDD and p,p{prime}-DDD by dog and bovine adrenal cortex as studied. Of the cortex subcellular fractions, the cytosol fraction was found to be the most active in metabolizing the substrates, followed by the mitochondrial fraction. This metabolism including that in cytosolic fractions, did not take place with boiled enzyme preparations and required an NADPH generating system. This study has been directed towards establishing the metabolic activation mechanism which may account for the adrenocorticolytic effect of mitotane in contrast to detoxication by the liver. HPLC and TLC metabolic profiles have been generated from incubations of bovine and dog adrenal cortex homogenates and their subfractions for {sup 14}C-labeled p,p{prime}-DDD, o,p{prime}-DDD and its monochloroethylene derivative, o,p{prime}-DDMU.
- Research Organization:
- Michigan Univ., Ann Arbor, MI (USA)
- OSTI ID:
- 6621251
- Resource Relation:
- Other Information: Thesis (Ph. D.)
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
ANTINEOPLASTIC DRUGS
METABOLISM
ENDOCRINE DISEASES
CHEMOTHERAPY
ADRENAL GLANDS
CARBON 14 COMPOUNDS
CARCINOMAS
CATTLE
DOGS
LIQUID COLUMN CHROMATOGRAPHY
MITOCHONDRIA
STRUCTURE-ACTIVITY RELATIONSHIPS
THIN-LAYER CHROMATOGRAPHY
TRACER TECHNIQUES
ANIMALS
BODY
CELL CONSTITUENTS
CHROMATOGRAPHY
DISEASES
DOMESTIC ANIMALS
DRUGS
ENDOCRINE GLANDS
GLANDS
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
MAMMALS
NEOPLASMS
ORGANOIDS
ORGANS
RUMINANTS
SEPARATION PROCESSES
THERAPY
VERTEBRATES
550501* - Metabolism- Tracer Techniques
550901 - Pathology- Tracer Techniques