Influence of pyridine and some pyridine derivatives on spectral properties of reduced microsomes and on microsomal drug metabolizing activity

Jonen, H. G.; Hüthwohl, B; Kahl, Regine; Kahl, Georg F.

doi:10.1016/0006-2952(74)90334-7

Cited by 48 publications

(3 citation statements)

References 22 publications

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“…Metyrapone, a dipyridyl heme ligand generally regarded as an effective inhibitor of cytochrome P-450 (Leibman & Ortiz, 1973;Testa & Jenner, 1981;Netter, 1980), especially that induced by phenobarbital (Jonen et al, 1974;Hultmark et al, 1979;Parkinson et al, 1982), was found to enhance several PB-1-catalyzed reactions in the reconstituted system. That the stimulatory effects of metyrapone on microsomal monooxygenations (Leibman, 1969;Leibman & Ortiz, 1973;Waxman et al, 1982) appear to be characteristic of PB-1preferred substrates indicates that PB-1 probably mediates the observed microsomal enhancements.…”

Section: Discussionmentioning

confidence: 99%

“…Metyrapone Enhancement of PB-1 Activities. Although metyrapone inhibits many P-450-catalyzed reactions [e.g., Jonen et al (1974) and Testa & Jenner (1981)], this dipyridyl heme ligand enhances (up to 2or 3-fold) the microsomal metabolism of trichloroethylene, acetanilide, and p-tolyl ethyl sulfide [yielding p-(hydroxymethyl)phenyl ethyl sulfide] (Leibman, 1969; Leibman & Ortiz, 1973; Waxman et al, 1982). Our present results (Table III) confirm these previous observations and suggest that this substrate-dependent metyrapone enhancement reflects the stimulation of P-450 PB-1 or of PB-1-like isozymes present in the microsomal fractions.…”

Section: V8-proteasementioning

confidence: 99%

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Cytochrome P-450 isozyme 1 from phenobarbital-induced rat liver: purification, characterization, and interactions with metyrapone and cytochrome b5

Waxman¹,

Walsh²

1983

Biochemistry

126

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Cytochrome P-450 isozyme 1 (PB-1) (Mr congruent to 53 000) was purified to apparent homogeneity from phenobarbital (PB)-induced rat liver microsomes, and its spectral, structural, immunochemical, and catalytic properties were determined. PB-1, present in significant amounts in uninduced rat liver microsomes, is induced approximately 2-4-fold by phenobarbital, as compared to the greater than 30-fold induction typical of the major PB isozymes characterized previously. PB-1 was distinguished from the major PB-induced isozymes PB-4 and PB-5 [Waxman, D. J., & Walsh, C. (1982) J. Biol. Chem. 257, 10446-10457] by the absence of a Fe2+-metyrapone P446 complex, by its unique NH2-terminal sequence and distinct peptide maps, by the lack of immuno-cross-reactivity to PB-4, and by its characteristic substrate-specificity profile. Metyrapone effected a saturable enhancement of several PB-1-catalyzed reactions in the reconstituted system [Km(metyrapone) congruent to 200 microM], which varied in magnitude with the substrate, with a maximal stimulation of 5-8-fold in the case of acetanilide 4-hydroxylation. That metyrapone enhanced the corresponding microsomal activities only in cases where the metyrapone-sensitive PB-4 did not catalyze the same reaction at significant rates suggested that PB-1 is probably responsible for the substrate-dependent stimulatory effects of metyrapone on microsomal monooxygenations. In contrast to PB-4 and PB-5, PB-1 was characterized by a marked, but not absolute, dependence on cytochrome b5 (b5) for catalytic activity, with 4-7-fold stimulations typically effected by inclusion of stoichiometric b5 in the reconstituted system. That these b5-stimulations were lipid dependent and were abolished with specific proteolytic fragments lacking b5's COOH-terminal membranous segment evidenced the importance of this segment for efficient, b5-mediated electron transfer to P-450 PB-1 in the reconstituted monooxygenase system.

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Section: Discussionmentioning

confidence: 99%

Section: V8-proteasementioning

confidence: 99%

Cytochrome P-450 isozyme 1 from phenobarbital-induced rat liver: purification, characterization, and interactions with metyrapone and cytochrome b5

Waxman¹,

Walsh²

1983

Biochemistry

126

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“…Protein concentrations were determined by the method of Lowry et al (1951). Metyrapone-binding spectral analysis Spectra produced on binding of metyrapone [2-methyl-1,2-bis-(pyrid-3-yl)propan-1-one] to cytochrome P-450 were determined by the method of Jonen et al (1974) with a Perkin-Elmer model 556 double-wavelength spectrophotometer. Binding constants were calculated from double-reciprocal plots of the difference (A446-A490) against metyrapone concentration.…”

Section: Solubilization Ofmicrosomal Membrane Vesiclesmentioning

confidence: 99%

Induction by phenobarbital of the mRNA for a specific variant of rat liver microsomal cytochrome P-450

Phillips¹,

Shephard²,

Mitani³

et al. 1981

Biochemical Journal

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The treatment of rats for 4 days with phenobarbital causes an apparent 3-fold increase in the amount of total liver cytochrome P-450. By sodium dodecyl sulphate/polyacrylamide-gel electrophoresis, metyrapone binding and immunoprecipitation, this increase was found to be due to a much larger increase in a restricted number of specific cytochrome P-450 variants. A radioimmunoassay technique demonstrated that the major phenobarbital-inducible variant, of molecular weight 52 000, is induced 24-fold by phenobarbital. Immunoprecipitation analysis of products of translation in vitro with an antibody specific to the 52 000-mol.wt. cytochrome P-450 showed that phenobarbital induces the mRNA in polyribosomes for this variant 20-fold. Evidence is presented for the action of phenobarbital at the transcriptional and translational levels.

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Reductive and oxidative metabolism of nitrofurantoin in rat liver

1980

Naunyn-Schmiedeberg's Arch. Pharmacol.

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Influence of pyridine and some pyridine derivatives on spectral properties of reduced microsomes and on microsomal drug metabolizing activity

Cited by 48 publications

References 22 publications

Cytochrome P-450 isozyme 1 from phenobarbital-induced rat liver: purification, characterization, and interactions with metyrapone and cytochrome b5

Cytochrome P-450 isozyme 1 from phenobarbital-induced rat liver: purification, characterization, and interactions with metyrapone and cytochrome b5

Induction by phenobarbital of the mRNA for a specific variant of rat liver microsomal cytochrome P-450

Reductive and oxidative metabolism of nitrofurantoin in rat liver

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