III. Nitrogenous Compounds as Ligands to Hemoporphyrins � The Concept of Metabolic-Intermediary Complexes

Lindeke, Björn; Paulsen-Sörman, Ulla

doi:10.1159/000415084

Cited by 4 publications

(2 citation statements)

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“…This is an intriguing finding, since the nitroso compound is generally believed to be the ultimate ligand. [3][4][5][6] Obviously, there are different factors governing metabolic events when the nitroso ligand is formed from its hydroxylamine precursor in the active site of the enzyme as compared with its direct addition into the incubation mixture.…”

Section: Substrate Interactions With Oxidized Microsomalmentioning

confidence: 99%

Cytochrome p‐455 nm complex formation in the metabolism of phenylalkylamines. XII. Enantioselectivity and temperature dependence in microsomes and reconstituted cytochrome p‐450 systems from rat liver

Jonsson

Lindeke

1992

Chirality

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Formation of metabolic intermediate (MI) complexes was studied with the enantiomers of amphetamine, 1-phenyl-2-pentanamine, N-hydroxyamphetamine, and 2-nitroso-1-phenylpropane (the C-nitroso analogue of amphetamine). Three different enzyme systems were used; liver microsomes from phenobarbital pretreated rats and two reconstituted systems containing the P450 2B1 and P450 2C11 forms of cytochrome P-450. Enantioselective complex formation in microsomes was shown for the amines and the nitroso compound, but not for the hydroxylamine. The highly purified P450 2B1 system formed the MI complex with all substrates tested, and the enantioselectivity observed with the microsomal system was reproduced. In the P450 2C11 system the nitroso compounds were completely inactive, whereas the enantiomers of N-hydroxyamphetamine still produced the complex at a high rate. Changes in temperature were shown to affect (R)-2-nitroso-1-phenylpropane more than its enantiomer. Both enantiomers showed biphasic Arrhenius plots for MI complex formation in microsomes (breaks around 22 degrees C), but the activation energies of the (R)-isomer were about five times higher than those of the (S)-isomer. A theory is presented which suggests different modes of interaction with the active site of P-450 to account for the different behaviour of the various substrates.

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Section: Substrate Interactions With Oxidized Microsomalmentioning

confidence: 99%

Cytochrome p‐455 nm complex formation in the metabolism of phenylalkylamines. XII. Enantioselectivity and temperature dependence in microsomes and reconstituted cytochrome p‐450 systems from rat liver

Jonsson

Lindeke

1992

Chirality

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“…The nitrone intermediate is susceptible to further oxidation to the corresponding nitroso derivative under CYTP450 catalysis. It is assumed that this nitroso derivative is the metabolic intermediate (MI) responsible for formation of a complex with the CYTP450, resulting in a (usually) reversible inhibition of the enzyme [199]. The binding of such metabolic intermediates to CYTP450 involves the presence of the enzyme in reduced form; under such conditions, the nitrogen atom will interact with the iron cation [200] (Figure 8.2): Many more studies have focused on the biotransformation of primary arylamines, given their toxicological significance.…”

Section: Selected Examplesmentioning

confidence: 99%

Drug Metabolism

2005

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Some properties of an inhibitory cytochrome P-450 metabolic-intermediate complex existing in a spin-state equilibrium

Hlavica¹,

Künzel²,

Achtert³

1989

Biochemical Pharmacology

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III. Nitrogenous Compounds as Ligands to Hemoporphyrins � The Concept of Metabolic-Intermediary Complexes

Cited by 4 publications

References 0 publications

Cytochrome p‐455 nm complex formation in the metabolism of phenylalkylamines. XII. Enantioselectivity and temperature dependence in microsomes and reconstituted cytochrome p‐450 systems from rat liver

Cytochrome p‐455 nm complex formation in the metabolism of phenylalkylamines. XII. Enantioselectivity and temperature dependence in microsomes and reconstituted cytochrome p‐450 systems from rat liver

Drug Metabolism

Some properties of an inhibitory cytochrome P-450 metabolic-intermediate complex existing in a spin-state equilibrium

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