Selective inhibition of rat hepatic microsomal cytochrome P-450. I. Effect of the in vivo administration of cimetidine
| Autor: | T, Chang, M, Levine, S M, Bandiera, G D, Bellward |
|---|---|
| Rok vydání: | 1992 |
| Předmět: |
Male
Oxidoreductases N-Demethylating Rats Inbred Strains Dexamethasone Rats Cytochrome P-450 Enzyme System Immunoglobulin G Cytochrome P-450 CYP2B1 Microsomes Liver Animals Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme Inhibitors Testosterone Aryl Hydrocarbon Hydroxylases Cimetidine Oxidoreductases Oxidation-Reduction Aminopyrine N-Demethylase |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 260(3) |
| ISSN: | 0022-3565 |
| Popis: | Cimetidine is considered to be a general inhibitor of cytochrome P-450 enzymes, but there is indirect evidence that certain cytochrome P-450 enzymes are not inhibited by cimetidine. The purpose of this study was to determine whether cimetidine, when administered in vivo to adult male Wistar rats, selectively inhibits hepatic microsomal cytochrome P-450 enzymes. Uninduced, phenobarbital (PB)-induced and dexamethasone (DEX)-induced rats were sacrificed 90 min after treatment with a single i.p. dose of cimetidine HCI (150 mg/kg) or saline. Hepatic microsomes were prepared, and aminopyrine N-demethylase (APND), pentoxyresorufin O-dealkylase (PROD), erythromycin N-demethylase (EMND) activities and oxidation of testosterone were determined. In addition, immunoinhibition studies with a polyclonal antibody monospecific for cytochrome P-450IIC11 were performed. Cimetidine treatment inhibited APND, PROD and EMND activities to a greater extent in microsomes from uninduced rats than in those from PB- or DEX-induced rats, suggesting that the induced cytochrome P-450 enzymes were less affected by cimetidine than were those in uninduced rats. Cimetidine treatment inhibited testosterone 2 alpha-hydroxylase activity by 65, 73 and 46%, respectively, in microsomes from uninduced, PB-induced and DEX-induced rats. The antibody completely inhibited testosterone 2 alpha-hydroxylase activity in the three groups of microsomes, indicating that this activity is specific for cytochrome P-450IIC11 in all these cases. Neither cimetidine treatment nor the antibody inhibited microsomal testosterone 2 beta-, 6 beta-, 7 alpha- or 16 beta-hydroxylase activity.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Databáze: | OpenAIRE |
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