Hepatic microsomal azoreductase activity: Reactivity of azo dye substrates is determined by their electron densities and redox potentials

S. Zbaida, Curtis F. Brewer, W. G. Levine

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Abstract

We have previously established that microsomal reduction of azo dyes requires polar electron-donating ring substituents [e.g. -OH, -NH2, - NHCH3, or -N(CH3)2]. Reduction of dyes substituted exclusively with such moieties on either phenyl ring is insensitive to both O2 and CO (I- substrates). In contrast, azoreduction of compounds containing additional electron-withdrawing substituents (e.g. -SO3H, -COOH, -COOCH3, and - AsO3H2) on the opposite (prime) phenyl ring is sensitive to both O2 and CO (S-substrates). We have recently shown that Hammett aromatic substituent constants and redox potentials of the dyes, determined by cyclic voltammetry (CV), distinguish between I- and S-substrates. Dyes that exhibit positive Hammett σ substituent constants on 1 of the 2 rings are S-substrates, and undergo immediate quenching of their one electron-reduced intermediates upon exposure to air, as observed by CV. In contrast, dyes that have negative Hammett σ values on one or both rings are I-substrates, and their one electron-reduced intermediates are relatively stable in air. In this study, we have investigated the susceptibility to microsomal azoreduction of monosubstituted dyes, with ring substituents possessing a wide range of Hammett σ values. We have observed a direct correlation between the susceptibility of these compounds to microsomal azoreduction and the Hammett σ constant of the aromatic ring substituent, and the presence of a positive potential in the dyes observed by CV. A Hammett σ value of -0.37 or lower is required for substrate activity. Dyes with two substituents in the prime ring confirmed the previous correlation of negative and positive Hammett σ values with I- and S-substrate activities, respectively. The results suggest that binding and reduction of azo compounds by different forms of microsomal cytochrome P-450 is regulated by the electron densities and redox potentials of the dyes.

Original languageEnglish (US)
Pages (from-to)412-418
Number of pages7
JournalDrug Metabolism and Disposition
Volume22
Issue number3
StatePublished - 1994

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Azo Compounds
Oxidation-Reduction
Carrier concentration
Coloring Agents
Electrons
Liver
Substrates
Cyclic voltammetry
Carbon Monoxide
Air
azoreductase
Cytochrome P-450 Enzyme System
Quenching

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

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title = "Hepatic microsomal azoreductase activity: Reactivity of azo dye substrates is determined by their electron densities and redox potentials",
abstract = "We have previously established that microsomal reduction of azo dyes requires polar electron-donating ring substituents [e.g. -OH, -NH2, - NHCH3, or -N(CH3)2]. Reduction of dyes substituted exclusively with such moieties on either phenyl ring is insensitive to both O2 and CO (I- substrates). In contrast, azoreduction of compounds containing additional electron-withdrawing substituents (e.g. -SO3H, -COOH, -COOCH3, and - AsO3H2) on the opposite (prime) phenyl ring is sensitive to both O2 and CO (S-substrates). We have recently shown that Hammett aromatic substituent constants and redox potentials of the dyes, determined by cyclic voltammetry (CV), distinguish between I- and S-substrates. Dyes that exhibit positive Hammett σ substituent constants on 1 of the 2 rings are S-substrates, and undergo immediate quenching of their one electron-reduced intermediates upon exposure to air, as observed by CV. In contrast, dyes that have negative Hammett σ values on one or both rings are I-substrates, and their one electron-reduced intermediates are relatively stable in air. In this study, we have investigated the susceptibility to microsomal azoreduction of monosubstituted dyes, with ring substituents possessing a wide range of Hammett σ values. We have observed a direct correlation between the susceptibility of these compounds to microsomal azoreduction and the Hammett σ constant of the aromatic ring substituent, and the presence of a positive potential in the dyes observed by CV. A Hammett σ value of -0.37 or lower is required for substrate activity. Dyes with two substituents in the prime ring confirmed the previous correlation of negative and positive Hammett σ values with I- and S-substrate activities, respectively. The results suggest that binding and reduction of azo compounds by different forms of microsomal cytochrome P-450 is regulated by the electron densities and redox potentials of the dyes.",
author = "S. Zbaida and Brewer, {Curtis F.} and Levine, {W. G.}",
year = "1994",
language = "English (US)",
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T1 - Hepatic microsomal azoreductase activity

T2 - Reactivity of azo dye substrates is determined by their electron densities and redox potentials

AU - Zbaida, S.

AU - Brewer, Curtis F.

AU - Levine, W. G.

PY - 1994

Y1 - 1994

N2 - We have previously established that microsomal reduction of azo dyes requires polar electron-donating ring substituents [e.g. -OH, -NH2, - NHCH3, or -N(CH3)2]. Reduction of dyes substituted exclusively with such moieties on either phenyl ring is insensitive to both O2 and CO (I- substrates). In contrast, azoreduction of compounds containing additional electron-withdrawing substituents (e.g. -SO3H, -COOH, -COOCH3, and - AsO3H2) on the opposite (prime) phenyl ring is sensitive to both O2 and CO (S-substrates). We have recently shown that Hammett aromatic substituent constants and redox potentials of the dyes, determined by cyclic voltammetry (CV), distinguish between I- and S-substrates. Dyes that exhibit positive Hammett σ substituent constants on 1 of the 2 rings are S-substrates, and undergo immediate quenching of their one electron-reduced intermediates upon exposure to air, as observed by CV. In contrast, dyes that have negative Hammett σ values on one or both rings are I-substrates, and their one electron-reduced intermediates are relatively stable in air. In this study, we have investigated the susceptibility to microsomal azoreduction of monosubstituted dyes, with ring substituents possessing a wide range of Hammett σ values. We have observed a direct correlation between the susceptibility of these compounds to microsomal azoreduction and the Hammett σ constant of the aromatic ring substituent, and the presence of a positive potential in the dyes observed by CV. A Hammett σ value of -0.37 or lower is required for substrate activity. Dyes with two substituents in the prime ring confirmed the previous correlation of negative and positive Hammett σ values with I- and S-substrate activities, respectively. The results suggest that binding and reduction of azo compounds by different forms of microsomal cytochrome P-450 is regulated by the electron densities and redox potentials of the dyes.

AB - We have previously established that microsomal reduction of azo dyes requires polar electron-donating ring substituents [e.g. -OH, -NH2, - NHCH3, or -N(CH3)2]. Reduction of dyes substituted exclusively with such moieties on either phenyl ring is insensitive to both O2 and CO (I- substrates). In contrast, azoreduction of compounds containing additional electron-withdrawing substituents (e.g. -SO3H, -COOH, -COOCH3, and - AsO3H2) on the opposite (prime) phenyl ring is sensitive to both O2 and CO (S-substrates). We have recently shown that Hammett aromatic substituent constants and redox potentials of the dyes, determined by cyclic voltammetry (CV), distinguish between I- and S-substrates. Dyes that exhibit positive Hammett σ substituent constants on 1 of the 2 rings are S-substrates, and undergo immediate quenching of their one electron-reduced intermediates upon exposure to air, as observed by CV. In contrast, dyes that have negative Hammett σ values on one or both rings are I-substrates, and their one electron-reduced intermediates are relatively stable in air. In this study, we have investigated the susceptibility to microsomal azoreduction of monosubstituted dyes, with ring substituents possessing a wide range of Hammett σ values. We have observed a direct correlation between the susceptibility of these compounds to microsomal azoreduction and the Hammett σ constant of the aromatic ring substituent, and the presence of a positive potential in the dyes observed by CV. A Hammett σ value of -0.37 or lower is required for substrate activity. Dyes with two substituents in the prime ring confirmed the previous correlation of negative and positive Hammett σ values with I- and S-substrate activities, respectively. The results suggest that binding and reduction of azo compounds by different forms of microsomal cytochrome P-450 is regulated by the electron densities and redox potentials of the dyes.

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