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Selective inhibition of rat hepatic microsomal cytochrome P-450. I. Effect of the in vivo administration of cimetidine.
J Pharmacol Exp Ther. 1992 Mar; 260(3):1441-9.JP

Abstract

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)

Authors+Show Affiliations

Chang T
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Levine M
No affiliation info available
Bandiera SM
No affiliation info available
Bellward GD
No affiliation info available

MeSH

Aminopyrine N-DemethylaseAnimalsAryl Hydrocarbon HydroxylasesCimetidineCytochrome P-450 CYP2B1Cytochrome P-450 CYP3ACytochrome P-450 Enzyme InhibitorsCytochrome P-450 Enzyme SystemDexamethasoneImmunoglobulin GMaleMicrosomes, LiverOxidation-ReductionOxidoreductasesOxidoreductases, N-DemethylatingRatsRats, Inbred StrainsTestosterone

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

1545403

Citation

Chang, T, et al. "Selective Inhibition of Rat Hepatic Microsomal Cytochrome P-450. I. Effect of the in Vivo Administration of Cimetidine." The Journal of Pharmacology and Experimental Therapeutics, vol. 260, no. 3, 1992, pp. 1441-9.
Chang T, Levine M, Bandiera SM, et al. Selective inhibition of rat hepatic microsomal cytochrome P-450. I. Effect of the in vivo administration of cimetidine. J Pharmacol Exp Ther. 1992;260(3):1441-9.
Chang, T., Levine, M., Bandiera, S. M., & Bellward, G. D. (1992). Selective inhibition of rat hepatic microsomal cytochrome P-450. I. Effect of the in vivo administration of cimetidine. The Journal of Pharmacology and Experimental Therapeutics, 260(3), 1441-9.
Chang T, et al. Selective Inhibition of Rat Hepatic Microsomal Cytochrome P-450. I. Effect of the in Vivo Administration of Cimetidine. J Pharmacol Exp Ther. 1992;260(3):1441-9. PubMed PMID: 1545403.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Selective inhibition of rat hepatic microsomal cytochrome P-450. I. Effect of the in vivo administration of cimetidine. AU - Chang,T, AU - Levine,M, AU - Bandiera,S M, AU - Bellward,G D, PY - 1992/3/1/pubmed PY - 1992/3/1/medline PY - 1992/3/1/entrez SP - 1441 EP - 9 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 260 IS - 3 N2 - 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) SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/1545403/Selective_inhibition_of_rat_hepatic_microsomal_cytochrome_P_450__I__Effect_of_the_in_vivo_administration_of_cimetidine_ DB - PRIME DP - Unbound Medicine ER -