Metabolism of DHEA by Cytochromes P450 in Rat and Human Liver Microsomal Fractions
Autor: | Ned B. Smith, William M. Pierce, Jennifer L. Fitzpatrick, Sharon L. Ripp, Russell A. Prough |
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Rok vydání: | 2001 |
Předmět: |
Adult
Male endocrine system medicine.medical_specialty Miconazole Metabolite Biophysics Dehydroepiandrosterone In Vitro Techniques Pharmacology Biology Biochemistry Mass Spectrometry Troleandomycin Rats Sprague-Dawley Hydroxylation chemistry.chemical_compound Cytochrome P-450 Enzyme System Internal medicine Cytochrome P-450 CYP3A polycyclic compounds medicine Animals Cytochrome P-450 Enzyme Inhibitors Humans skin and connective tissue diseases Molecular Biology Benzoflavones Cytochrome P450 Oxidoreductases N-Demethylating Metabolism Middle Aged Rats Endocrinology chemistry Microsomes Liver biology.protein Microsome Aryl Hydrocarbon Hydroxylases human activities hormones hormone substitutes and hormone antagonists Chromatography Liquid medicine.drug |
Zdroj: | Archives of Biochemistry and Biophysics. 389:278-287 |
ISSN: | 0003-9861 |
Popis: | Administration of dehydroepiandrosterone (DHEA) to rodents produces many unique biological responses, some of which may be due to metabolism of DHEA to more biologically active products. In the current study, DHEA metabolism was studied using human and rat liver microsomal fractions. In both species, DHEA was extensively metabolized to multiple products; formation of these products was potently inhibited in both species by miconazole, demonstrating a principal role for cytochrome P450. In the rat, use of P450 form-selective inhibitors suggested the participation of P4501A and 3A forms in DHEA metabolism. Human liver samples displayed interindividual differences in that one of five subjects metabolized DHEA to a much greater extent than the others. This difference correlated with the level of P4503A activity present in the human liver samples. For one subject, troleandomycin inhibited hepatic microsomal metabolism of DHEA by 78%, compared to 81% inhibition by miconazole, suggesting the importance of P4503A in these reactions. Form-selective inhibitors of P4502D6 and P4502E1 had a modest inhibitory effect, suggesting that these forms may also contribute to metabolism of DHEA in humans. Metabolites identified by LC-MS in both species included 16alpha-hydroxy-DHEA, 7alpha-hydroxy-DHEA, and 7-oxo-DHEA. While 16alpha-hydroxy-DHEA appeared to be the major metabolite produced in rat, the major metabolite produced in humans was a mono-hydroxylated DHEA species, whose position of hydroxylation is unknown. |
Databáze: | OpenAIRE |
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