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Inhibition and induction of rabbit liver microsomal cytochrome P-450 by pyridine.
J Pharmacol Exp Ther. 1987 Oct; 243(1):384-90.JP

Abstract

The effects of acute and chronic administration of pyridine (PY) on rabbit hepatic microsomal cytochrome P-450-catalyzed drug metabolism have been examined. PY inhibited cytochrome P-450-catalyzed drug metabolism in vitro and in vivo. Noncompetitive inhibition of microsomal drug metabolism was observed with inhibitory constant (Ki) values ranging between 2.0 and 6.0 mM. Acute PY administration, 100 mg/kg i.p., prolonged hexobarbital sleep time in rats 2.5-fold. Chronic administration of PY to rabbits resulted in increased hepatic microsomal cytochrome P-450 content, with induction of different form(s) exhibiting elevated catalytic activities toward PY, N-nitrosodimethylamine, alcohols and aniline. PY administration (100 mg/kg i.p. for 5 days) to rabbits increased hepatic microsomal cytochrome P-450 content over 2-fold relative to uninduced animals. Sodium dodecylsulfate-polyacrylamide gel electrophoresis of PY-induced microsomes revealed protein bands of enhanced intensity occurring in the regions of P-450 LM3 and LM4. Both PY- and imidazole-induced microsomes were effective in the production of PY N-oxide, with Vmax values of 1.6 and 1.8 nmol/min/mg of protein, respectively. When rates were normalized for P-450 content, PY- and imidazole-induced microsomes produced 0.9 nmol of PY N-oxide/min/nmol of P-450, comparable to that obtained for PB-induced suspensions. N-nitrosodimethylamine N-demethylase activity was enhanced 2.5- and 6-fold relative to PB- and beta-naphthoflavone-induced microsomes, respectively. A single low KM value of 0.17 mM was obtained for N-nitrosodimethylamine N-demethylase activity in PY-induced microsomes; in contrast PB- and beta-naphthoflavone-induced microsomes yielded biphasic kinetics.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors+Show Affiliations

Kaul KL
Department of Pharmacology, Northwestern University Medical School, Chicago, Illinois.
Novak RF
No affiliation info available

MeSH

AnimalsCytochrome P-450 Enzyme InhibitorsCytochrome P-450 Enzyme SystemDimethylnitrosamineEnzyme InductionEthanolHexobarbitalKineticsMaleMicrosomes, LiverNADPOxidation-ReductionPyridinesRabbitsRatsRats, Inbred StrainsSleep

Pub Type(s)

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

Language

eng

PubMed ID

3668864

Citation

Kaul, K L., and R F. Novak. "Inhibition and Induction of Rabbit Liver Microsomal Cytochrome P-450 By Pyridine." The Journal of Pharmacology and Experimental Therapeutics, vol. 243, no. 1, 1987, pp. 384-90.
Kaul KL, Novak RF. Inhibition and induction of rabbit liver microsomal cytochrome P-450 by pyridine. J Pharmacol Exp Ther. 1987;243(1):384-90.
Kaul, K. L., & Novak, R. F. (1987). Inhibition and induction of rabbit liver microsomal cytochrome P-450 by pyridine. The Journal of Pharmacology and Experimental Therapeutics, 243(1), 384-90.
Kaul KL, Novak RF. Inhibition and Induction of Rabbit Liver Microsomal Cytochrome P-450 By Pyridine. J Pharmacol Exp Ther. 1987;243(1):384-90. PubMed PMID: 3668864.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition and induction of rabbit liver microsomal cytochrome P-450 by pyridine. AU - Kaul,K L, AU - Novak,R F, PY - 1987/10/1/pubmed PY - 1987/10/1/medline PY - 1987/10/1/entrez SP - 384 EP - 90 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 243 IS - 1 N2 - The effects of acute and chronic administration of pyridine (PY) on rabbit hepatic microsomal cytochrome P-450-catalyzed drug metabolism have been examined. PY inhibited cytochrome P-450-catalyzed drug metabolism in vitro and in vivo. Noncompetitive inhibition of microsomal drug metabolism was observed with inhibitory constant (Ki) values ranging between 2.0 and 6.0 mM. Acute PY administration, 100 mg/kg i.p., prolonged hexobarbital sleep time in rats 2.5-fold. Chronic administration of PY to rabbits resulted in increased hepatic microsomal cytochrome P-450 content, with induction of different form(s) exhibiting elevated catalytic activities toward PY, N-nitrosodimethylamine, alcohols and aniline. PY administration (100 mg/kg i.p. for 5 days) to rabbits increased hepatic microsomal cytochrome P-450 content over 2-fold relative to uninduced animals. Sodium dodecylsulfate-polyacrylamide gel electrophoresis of PY-induced microsomes revealed protein bands of enhanced intensity occurring in the regions of P-450 LM3 and LM4. Both PY- and imidazole-induced microsomes were effective in the production of PY N-oxide, with Vmax values of 1.6 and 1.8 nmol/min/mg of protein, respectively. When rates were normalized for P-450 content, PY- and imidazole-induced microsomes produced 0.9 nmol of PY N-oxide/min/nmol of P-450, comparable to that obtained for PB-induced suspensions. N-nitrosodimethylamine N-demethylase activity was enhanced 2.5- and 6-fold relative to PB- and beta-naphthoflavone-induced microsomes, respectively. A single low KM value of 0.17 mM was obtained for N-nitrosodimethylamine N-demethylase activity in PY-induced microsomes; in contrast PB- and beta-naphthoflavone-induced microsomes yielded biphasic kinetics.(ABSTRACT TRUNCATED AT 250 WORDS) SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/3668864/Inhibition_and_induction_of_rabbit_liver_microsomal_cytochrome_P_450_by_pyridine_ DB - PRIME DP - Unbound Medicine ER -