In vitro formation of an inhibitory complex between an isosafrole metabolite and rat hepatic cytochrome P-450 PB-B.
Drug Metab Dispos. 1989 Jul-Aug; 17(4):449-54.DM

Abstract

A series of in vitro studies was performed, in rat liver microsomes, in which metabolite intermediate (MI) complexation of cytochrome P-450 (P-450) by the methylenedioxyphenyl compound isosafrole was related to P-450 isozyme-specific inhibition of drug oxidation. The C19-steroid androst-4-ene-3,17-dione was selected for initial study because the stereoselective hydroxylation of this substrate is specific for certain P-450s. In control microsomes only the 6 beta- and 16 beta-hydroxylations of the steroid (catalyzed, respectively, by the P-450s PCN-E and PB-B) were inhibited by isosafrole (I50 = 100 and 110 microM). In contrast, the 7 alpha- and 16 alpha-hydroxylases (P-450 UT-F- and UT-A-mediated, respectively) were refractory to inhibition. After phenobarbital (PB) induction, steroid 6 beta- and 16 beta-hydroxylase activities were again inhibited (I50 = 170 and 190 microM) but, in addition, the 16 alpha-hydroxylase pathway was also inhibited (I50 = 200 microM). Spectral studies revealed that MI complexation of P-450 in untreated microsomes was minimal but was enhanced markedly after PB induction (up to 50% of the total P-450 content complexed). Thus, it is apparent that a PB-inducible P-450 is involved in MI complex formation under these conditions. Indeed the I50 of isosafrole toward steroid 16 beta-hydroxylase activity was decreased if the inhibitor was preincubated with NADPH-fortified PB-induced microsomes prior to substrate addition; the preincubation step did not enhance the inhibition of any other steroid hydroxylase pathway by isosafrole.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors+Show Affiliations

Murray M

Department of Medicine, University of Sydney, Westmead Hospital.

Reidy GF

No affiliation info available

MeSH

AnimalsBiotransformationCytochrome P-450 Enzyme InhibitorsCytochrome P-450 Enzyme SystemDioxolesEnzyme InductionImmunoglobulin GIn Vitro TechniquesIsoenzymesMaleMicrosomes, LiverMixed Function OxygenasesOxidation-ReductionRatsRats, Inbred StrainsSafrole

Pub Type(s)

Journal Article

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

Language

eng

PubMed ID

2571488

Citation

Murray, M, and G F. Reidy. "In Vitro Formation of an Inhibitory Complex Between an Isosafrole Metabolite and Rat Hepatic Cytochrome P-450 PB-B." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 17, no. 4, 1989, pp. 449-54.

Murray M, Reidy GF. In vitro formation of an inhibitory complex between an isosafrole metabolite and rat hepatic cytochrome P-450 PB-B. Drug Metab Dispos. 1989;17(4):449-54.

Murray, M., & Reidy, G. F. (1989). In vitro formation of an inhibitory complex between an isosafrole metabolite and rat hepatic cytochrome P-450 PB-B. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 17(4), 449-54.

Murray M, Reidy GF. In Vitro Formation of an Inhibitory Complex Between an Isosafrole Metabolite and Rat Hepatic Cytochrome P-450 PB-B. Drug Metab Dispos. 1989 Jul-Aug;17(4):449-54. PubMed PMID: 2571488.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - In vitro formation of an inhibitory complex between an isosafrole metabolite and rat hepatic cytochrome P-450 PB-B. AU - Murray,M, AU - Reidy,G F, PY - 1989/7/1/pubmed PY - 1989/7/1/medline PY - 1989/7/1/entrez SP - 449 EP - 54 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 17 IS - 4 N2 - A series of in vitro studies was performed, in rat liver microsomes, in which metabolite intermediate (MI) complexation of cytochrome P-450 (P-450) by the methylenedioxyphenyl compound isosafrole was related to P-450 isozyme-specific inhibition of drug oxidation. The C19-steroid androst-4-ene-3,17-dione was selected for initial study because the stereoselective hydroxylation of this substrate is specific for certain P-450s. In control microsomes only the 6 beta- and 16 beta-hydroxylations of the steroid (catalyzed, respectively, by the P-450s PCN-E and PB-B) were inhibited by isosafrole (I50 = 100 and 110 microM). In contrast, the 7 alpha- and 16 alpha-hydroxylases (P-450 UT-F- and UT-A-mediated, respectively) were refractory to inhibition. After phenobarbital (PB) induction, steroid 6 beta- and 16 beta-hydroxylase activities were again inhibited (I50 = 170 and 190 microM) but, in addition, the 16 alpha-hydroxylase pathway was also inhibited (I50 = 200 microM). Spectral studies revealed that MI complexation of P-450 in untreated microsomes was minimal but was enhanced markedly after PB induction (up to 50% of the total P-450 content complexed). Thus, it is apparent that a PB-inducible P-450 is involved in MI complex formation under these conditions. Indeed the I50 of isosafrole toward steroid 16 beta-hydroxylase activity was decreased if the inhibitor was preincubated with NADPH-fortified PB-induced microsomes prior to substrate addition; the preincubation step did not enhance the inhibition of any other steroid hydroxylase pathway by isosafrole.(ABSTRACT TRUNCATED AT 250 WORDS) SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/2571488/In_vitro_formation_of_an_inhibitory_complex_between_an_isosafrole_metabolite_and_rat_hepatic_cytochrome_P_450_PB_B_ DB - PRIME DP - Unbound Medicine ER -

Tags

In vitro formation of an inhibitory complex between an isosafrole metabolite and rat hepatic cytochrome P-450 PB-B.Drug Metab Dispos. 1989 Jul-Aug; 17(4):449-54.DM