Biomaterial Database

Dose-dependent actions of spironolactone on the inner and outer zones of the guinea pig adrenal cortex. 1992

D C Kossor, and H D Colby

Department of Pharmacology and Toxicology, Philadelphia College of Pharmacy and Science, Pa. 19104.

The results of prior in vitro studies indicated that spironolactone (SL) caused far greater degradation of cytochromes P-450 in the outer (zona glomerulosa plus zona fasciculata) than inner (zona reticularis) zone of the guinea pig adrenal cortex and selectively decreased microsomal 17 alpha-hydroxylase activity. Studies were done to determine if the effects of SL in vivo were similarly zone and/or enzyme selective. Administration of high doses of SL (100 mg/kg) to guinea pigs altered the gross appearance of the adrenal glands and caused declines in 17 alpha- and 21-hydroxylase activities in both inner and outer zone microsomal preparations. The losses in enzyme activities were accompanied by decreases in microsomal cytochrome P-450, cytochrome b5 and heme concentrations, and in mitochondrial P-450 levels in both zones. Microsomal P-450(17 alpha) apoprotein levels were also decreased in both zones. A lower dose (25 mg/kg) of SL did not affect adrenal morphology, but decreased microsomal P-450 levels in both zones. Neither mitochondrial P-450 nor microsomal b5 concentrations were affected in either zone. 17 alpha-Hydroxylase activities and P-450(17 alpha) apoprotein concentrations in both zones were decreased by the lower dose of SL, but 21-hydroxylase activity declined in the inner zone only. The results indicate that very high doses of SL have a variety of nonspecific effects on the adrenals which may be the consequence of drug toxicity. Nontoxic doses exert more selective effects on microsomal cytochromes P-450 in both adrenal zones, more closely mimicking the in vitro actions of the drug.

UI	MeSH Term	Description	Entries
D007274	Injections, Intraperitoneal	Forceful administration into the peritoneal cavity of liquid medication, nutrient, or other fluid through a hollow needle piercing the abdominal wall.	Intraperitoneal Injections,Injection, Intraperitoneal,Intraperitoneal Injection
D008297	Male		Males
D008861	Microsomes	Artifactual vesicles formed from the endoplasmic reticulum when cells are disrupted. They are isolated by differential centrifugation and are composed of three structural features: rough vesicles, smooth vesicles, and ribosomes. Numerous enzyme activities are associated with the microsomal fraction. (Glick, Glossary of Biochemistry and Molecular Biology, 1990; from Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed)	Microsome
D008928	Mitochondria	Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive RIBOSOMES, transfer RNAs (RNA, TRANSFER); AMINO ACYL T RNA SYNTHETASES; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs (RNA, MESSENGER). Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. (King & Stansfield, A Dictionary of Genetics, 4th ed)	Mitochondrial Contraction,Mitochondrion,Contraction, Mitochondrial,Contractions, Mitochondrial,Mitochondrial Contractions
D003577	Cytochrome P-450 Enzyme System	A superfamily of hundreds of closely related HEMEPROTEINS found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (MIXED FUNCTION OXYGENASES). In animals, these P-450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (BIOTRANSFORMATION). They are classified, according to their sequence similarities rather than functions, into CYP gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the CYP1, CYP2, and CYP3 gene families are responsible for most drug metabolism.	Cytochrome P-450,Cytochrome P-450 Enzyme,Cytochrome P-450-Dependent Monooxygenase,P-450 Enzyme,P450 Enzyme,CYP450 Family,CYP450 Superfamily,Cytochrome P-450 Enzymes,Cytochrome P-450 Families,Cytochrome P-450 Monooxygenase,Cytochrome P-450 Oxygenase,Cytochrome P-450 Superfamily,Cytochrome P450,Cytochrome P450 Superfamily,Cytochrome p450 Families,P-450 Enzymes,P450 Enzymes,Cytochrome P 450,Cytochrome P 450 Dependent Monooxygenase,Cytochrome P 450 Enzyme,Cytochrome P 450 Enzyme System,Cytochrome P 450 Enzymes,Cytochrome P 450 Families,Cytochrome P 450 Monooxygenase,Cytochrome P 450 Oxygenase,Cytochrome P 450 Superfamily,Enzyme, Cytochrome P-450,Enzyme, P-450,Enzyme, P450,Enzymes, Cytochrome P-450,Enzymes, P-450,Enzymes, P450,Monooxygenase, Cytochrome P-450,Monooxygenase, Cytochrome P-450-Dependent,P 450 Enzyme,P 450 Enzymes,P-450 Enzyme, Cytochrome,P-450 Enzymes, Cytochrome,Superfamily, CYP450,Superfamily, Cytochrome P-450,Superfamily, Cytochrome P450
D004305	Dose-Response Relationship, Drug	The relationship between the dose of an administered drug and the response of the organism to the drug.	Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D006168	Guinea Pigs	A common name used for the genus Cavia. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research.	Cavia,Cavia porcellus,Guinea Pig,Pig, Guinea,Pigs, Guinea
D000302	Adrenal Cortex	The outer layer of the adrenal gland. It is derived from MESODERM and comprised of three zones (outer ZONA GLOMERULOSA, middle ZONA FASCICULATA, and inner ZONA RETICULARIS) with each producing various steroids preferentially, such as ALDOSTERONE; HYDROCORTISONE; DEHYDROEPIANDROSTERONE; and ANDROSTENEDIONE. Adrenal cortex function is regulated by pituitary ADRENOCORTICOTROPIN.	Cortex, Adrenal
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D013148	Spironolactone	A potassium sparing diuretic that acts by antagonism of aldosterone in the distal renal tubules. It is used mainly in the treatment of refractory edema in patients with congestive heart failure, nephrotic syndrome, or hepatic cirrhosis. Its effects on the endocrine system are utilized in the treatments of hirsutism and acne but they can lead to adverse effects. (From Martindale, The Extra Pharmacopoeia, 30th ed, p827)	Spirolactone,Aldactone,Aldactone A,Aquareduct,Duraspiron,Espironolactona Alter,Espironolactona Mundogen,Flumach,Frumikal,Jenaspiron,Novo-Spiroton,Practon,SC-9420,Spiractin,Spiro L.U.T.,Spiro Von Ct,Spirobeta,Spirogamma,Spirolang,Spirono-Isis,Spironone,Spirospare,Veroshpiron,Verospiron,Verospirone,Ct, Spiro Von,Novo Spiroton,NovoSpiroton,SC 9420,SC9420,Spirono Isis,Von Ct, Spiro