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Selective inhibition of rat hepatic microsomal cytochrome P-450. II. Effect of the in vitro administration of cimetidine.
J Pharmacol Exp Ther. 1992 Mar; 260(3):1450-5.JP

Abstract

The purpose of this study was to determine whether the differential inhibition of rat hepatic microsomal cytochrome P-450 in adult male rats by in vivo cimetidine administration is observed when the drug is administered in vitro. Cimetidine, at concentrations of up to 10 mM, did not affect the catalytic function of cytochrome P-450IIA1 as measured by testosterone 7 alpha-hydroxylase activity. In contrast, it did inhibit activities that are specific for cytochromes P-450IIC11 (testosterone 2 alpha-hydroxylase activity), P-450IIB1/2 (testosterone 16 beta-hydroxylase activity) and P-450IIA1/2 (testosterone 2 beta- and 6 beta-hydroxylase activities), with IC50 values in the range of 1.0 to 7.4 mM. To further investigate the inhibition of cytochrome P-450 enzymes by in vitro cimetidine, preincubation experiments were performed. Hepatic microsomes were preincubated with a low concentration (0.05 mM) of cimetidine and 1 mM NADPH for 15 min before the initiation of substrate (testosterone) oxidation. Under these conditions, cimetidine resulted in the inhibition of the enzyme activities specific for cytochrome P-450IIC11, but it had no effect on those specific for cytochromes P-450IIA1, P-450IIB1/2 and P-450IIIA1/2. This differential inhibition by in vitro cimetidine required the presence of NADPH in the preincubation medium, suggesting that a catalysis-dependent process is involved. Therefore, preincubation of hepatic microsomes with NADPH and a relatively low concentration (0.05 mM) of cimetidine in vitro results in a pattern of inhibition of cytochrome P-450 enzymes similar to that which occurs after the in vivo administration of cimetidine reported in the previous study (Chang et al., 1992).

Authors+Show Affiliations

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

MeSH

AnimalsCimetidineCytochrome P-450 Enzyme InhibitorsIn Vitro TechniquesMaleMicrosomes, LiverMorphineNADPRatsRats, Inbred StrainsSteroid HydroxylasesTestosterone

Pub Type(s)

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

Language

eng

PubMed ID

1545404

Citation

Chang, T, et al. "Selective Inhibition of Rat Hepatic Microsomal Cytochrome P-450. II. Effect of the in Vitro Administration of Cimetidine." The Journal of Pharmacology and Experimental Therapeutics, vol. 260, no. 3, 1992, pp. 1450-5.
Chang T, Levine M, Bellward GD. Selective inhibition of rat hepatic microsomal cytochrome P-450. II. Effect of the in vitro administration of cimetidine. J Pharmacol Exp Ther. 1992;260(3):1450-5.
Chang, T., Levine, M., & Bellward, G. D. (1992). Selective inhibition of rat hepatic microsomal cytochrome P-450. II. Effect of the in vitro administration of cimetidine. The Journal of Pharmacology and Experimental Therapeutics, 260(3), 1450-5.
Chang T, Levine M, Bellward GD. Selective Inhibition of Rat Hepatic Microsomal Cytochrome P-450. II. Effect of the in Vitro Administration of Cimetidine. J Pharmacol Exp Ther. 1992;260(3):1450-5. PubMed PMID: 1545404.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Selective inhibition of rat hepatic microsomal cytochrome P-450. II. Effect of the in vitro administration of cimetidine. AU - Chang,T, AU - Levine,M, AU - Bellward,G D, PY - 1992/3/1/pubmed PY - 1992/3/1/medline PY - 1992/3/1/entrez SP - 1450 EP - 5 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 260 IS - 3 N2 - The purpose of this study was to determine whether the differential inhibition of rat hepatic microsomal cytochrome P-450 in adult male rats by in vivo cimetidine administration is observed when the drug is administered in vitro. Cimetidine, at concentrations of up to 10 mM, did not affect the catalytic function of cytochrome P-450IIA1 as measured by testosterone 7 alpha-hydroxylase activity. In contrast, it did inhibit activities that are specific for cytochromes P-450IIC11 (testosterone 2 alpha-hydroxylase activity), P-450IIB1/2 (testosterone 16 beta-hydroxylase activity) and P-450IIA1/2 (testosterone 2 beta- and 6 beta-hydroxylase activities), with IC50 values in the range of 1.0 to 7.4 mM. To further investigate the inhibition of cytochrome P-450 enzymes by in vitro cimetidine, preincubation experiments were performed. Hepatic microsomes were preincubated with a low concentration (0.05 mM) of cimetidine and 1 mM NADPH for 15 min before the initiation of substrate (testosterone) oxidation. Under these conditions, cimetidine resulted in the inhibition of the enzyme activities specific for cytochrome P-450IIC11, but it had no effect on those specific for cytochromes P-450IIA1, P-450IIB1/2 and P-450IIIA1/2. This differential inhibition by in vitro cimetidine required the presence of NADPH in the preincubation medium, suggesting that a catalysis-dependent process is involved. Therefore, preincubation of hepatic microsomes with NADPH and a relatively low concentration (0.05 mM) of cimetidine in vitro results in a pattern of inhibition of cytochrome P-450 enzymes similar to that which occurs after the in vivo administration of cimetidine reported in the previous study (Chang et al., 1992). SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/1545404/Selective_inhibition_of_rat_hepatic_microsomal_cytochrome_P_450__II__Effect_of_the_in_vitro_administration_of_cimetidine_ DB - PRIME DP - Unbound Medicine ER -