Drugs as Suicide Substrates of Cytochrome P-450

Matteis, Federico De

doi:10.1007/978-1-349-08759-4_8

Cited by 5 publications

(3 citation statements)

References 66 publications

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“…Where necessary hematin was added to give a final concentration of 2 pM. Samples of the assay mixture were incubated at 37°C with shaking for 0, 15,30,45,60, and 75 min in an oxygen atmosphere. The reaction was interrupted by adding 2 mL of 0.9 M trichloroacetic acid (TCA).…”

Section: Biochemical Assaysmentioning

confidence: 99%

“…Two mechanisms have been proposed: in one, metals produce peroxidative damage to microsomal membranes, leading to a conversion of cytochrome P-450 into cytochrome P-420. This would result in less heme being retained or accepted due to a loss of stable apoprotein structure, finally leading to a substrate-mediated induction (15). Alternatively, metal ions could directly regulate the cellular content of heme, and thus of hemoproteins, by mimicking the regulatory effects of heme on the enzymes of heme metabolism (5).…”

Section: Introductionmentioning

confidence: 99%

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Sodium arsenite induced alterations in bilirubin excretion and heme metabolism

Albores

Cebrián

Bach

et al. 1989

J. Biochem. Toxicol.

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The acute administration of sodium arsenite (AsIII) to rats resulted in a biphasic alteration of the hepatic cytosolic "free" heme pool. The first stage was an increase in the cytosolic "free" heme without significant effects on the content of cytochrome P-450 or on bilirubin excretion. The second stage consisted of a continuous fall of the cytosolic "free" heme and of the content of cytochrome P-450. These changes were concurrent with an eight-fold increase in heme oxygenase activity and associated with marked elevations in the biliary excretion of bilirubin. The bile was collected from chronically cannulated rats to avoid artifacts related to anesthesia or post anesthetic effects. The rapid increase in biliary excretion of labeled heme degradation products indicated an increased breakdown of newly synthesized heme. Immunoelectrophoresis of bile proteins showed an altered pattern of bile protein excretion. The increased biliary haptoglobin suggested some hemolysis, while the reduction in the free immunoglobulin A (IgA) secretory component showed an AsIII-related decreased protein transport across hepatocytes to bile. Further research is required to assess the direct role of an increased heme degradation in the genesis of the hepatotoxic effects of AsIII.

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Section: Biochemical Assaysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sodium arsenite induced alterations in bilirubin excretion and heme metabolism

Albores

Cebrián

Bach

et al. 1989

J. Biochem. Toxicol.

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“…Similarly, methylation of H 2 15 was investigated. N 21 -mono-(15m) and N 21 ,N 22 -dimethylation ([15d] + ) have been previously reported, [15,21] thus porphyrin H 2 15 was treated under condition b to target the N 21 ,N 22 ,N 23 -trimethylated species. However, under the conditions applied, the N 21 ,N 22 -dimethylated salt [15d] + was quantitatively obtained.…”

Section: Synthesismentioning

confidence: 99%

Nonplanar Porphyrins by N‐Substitution: A Neglected Pathway

et al. 2018

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N‐substitution of porphyrins has been a neglected route towards nonplanar porphyrins for the past decades. Previously, they featured in a host of potential medicinal and biochemical applications. However, tailored syntheses of N‐methylated porphyrins, improvements of synthetic methodology, or full conformational analyses were lacking since the initial studies. Here we investigated and optimized synthetic pathways to generate specific N‐methylated porphyrins exclusively and in good yields. Full characterizations of the spectroscopy and structural properties associated with the insertion of different numbers of methyl into the porphyrin core of 5,10,15,20‐tetrasubstituted A4‐ and 5,15‐disubstituted A2‐type porphyrins was carried out by using UV/Vis, NMR, and X‐ray crystallographic techniques. The latter, in conjunction with detailed normal structural decomposition analyses, identified the structural consequences of number and isomeric pattern of N‐methylation in terms of macrocycle nonplanarity and the underlying out‐of‐plane and in‐plane distortion modes.

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Interactions of Monoamine Oxidase Inhibitors, N-Acetylenic Analogues of Tryptamine, with Rat Liver Microsomal Cytochrome P450

Valoti

Costanzo

Sgaragli

et al. 1994

Journal of Pharmacy and Pharmacology

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Interactions between some novel and potent monoamine oxidase inhibitors (MAOIs), acetylenic analogues of tryptamine, and rat liver microsomal cytochrome P450 (P450) as evidenced by visible spectra analysis were analysed. Compounds with a secondary aliphatic amine moiety throughout induced type II difference spectra and exhibited the highest affinity for P450, whereas tertiary amines induced type I spectral changes and showed diminished affinity. P450 dependent aniline hydroxylase activity was inhibited by all compounds in an irreversible time-dependent manner. Only tertiary aliphatic amines constituted the substrate for P450-dependent N-demethylase activity, with comparable kinetic parameters. The N-demethylated metabolites were identified by thin-layer chromatography and mass-spectrometric analyses. These findings describe the role of P450-dependent microsomal mono-oxygenase systems in the metabolism of some MAOI acetylenic tryptamine derivatives and the possible hepatic contribution to adverse interactions between MAOIs, endobiotics and sympathomimetic compounds.

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Drugs as Suicide Substrates of Cytochrome P-450

Cited by 5 publications

References 66 publications

Sodium arsenite induced alterations in bilirubin excretion and heme metabolism

Sodium arsenite induced alterations in bilirubin excretion and heme metabolism

Nonplanar Porphyrins by N‐Substitution: A Neglected Pathway

Interactions of Monoamine Oxidase Inhibitors, N-Acetylenic Analogues of Tryptamine, with Rat Liver Microsomal Cytochrome P450

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