Use of spin traps to elucidate radical mechanisms of oxidations by hydroperoxides catalyzed by hemeproteins

1982 ◽  
Vol 60 (12) ◽  
pp. 1463-1473 ◽  
Author(s):  
Brenda Walker Griffin
Keyword(s):  
Membrane Lipids ◽  
Liver Microsomes ◽  
Cumene Hydroperoxide ◽  
Significant Inhibition ◽  
Nitroso Compounds ◽  
Spin Adduct ◽  
Methyl Radical ◽  
Radical Product ◽  
Spin Traps ◽  
Catalytic Function

The use of the spin traps nitrosobenzene and 2-methyl-2-nitrosopropane has established that metmyoglobin and liver microsomal cytochrome P-450 initiate a radical decomposition of cumene hydroperoxide. With metmyoglobin and the alkyl nitroso compound, the only radical product of cumene hydroperoxide trapped was the methyl radical formed by β scission of the cumyloxy radical. With both hemeprotein initiators, nitrosobenzene trapped only the cumyl radical, considered to be a decomposition product of the unstable spin adduct phenylcumyloxynitroxide. Support for this proposal includes: (1) previous spin trapping studies of the chemical decomposition of cumene hydroperoxide; and (2) significant inhibition by nitrosobenzene of the one-electron oxidation of aminopyrine and the autoxidation of unsaturated membrane lipids resulting from addition of the hydroperoxide to liver microsomes. Aminopyrine altered the epr signal amplitudes of the spin adducts produced with both nitroso compounds, indicative of oxidation of aminopyrine by the methyl radical and reduction of cumene hydroperoxide by the aminopyrine radical. The participation of hydroperoxide-derived radicals in the low peroxidatic activities of certain hemeproteins is quite distinct from the catalytic function of the true hemeprotein peroxidases, which bring about an efficient two-electron reduction of specific hydroperoxides.

Spin trapping by use of nitrosodurene and its derivatives

1982 ◽  
Vol 60 (12) ◽  
pp. 1532-1541 ◽  
Author(s):  
Ryusei Konaka ◽  
Shigeru Terabe ◽  
Taiichi Mizuta ◽  
Shigeru Sakata
Keyword(s):  
Hydrogen Peroxide ◽  
Esr Spectra ◽  
Spin Trapping ◽  
Nitroso Compounds ◽  
Spin Adduct ◽  
Spin Traps ◽  
Spectral Pattern ◽  
Alkyl Radicals ◽  
Alkyl Hydroperoxides ◽  
Tert Butyl Hydroperoxide

In spin trapping the N-methyl-N-phenylaminomethyl radical with nitrosodurene, an esr spectmm exhibiting line width alternation was observed despite the normal spectral pattern found with the use of nitroso-tert-butane. Nitrosodurene derivatives, N-duryl nitrone and methyl N-duryl nitrone, have been revealed to be other excellent spin traps for the N-, 0-, and S-centered radicals. Spin adducts of these radicals, which can be independently prepared by spin trapping with nitrosodurene, are stable and can be easily discriminated by large differences in β-hydrogen splittings or characteristic patterns. Methyl N-duryl nitrone reacted with tert-butyl hydroperoxide to give a spin adduct which could be clearly distinguished in the esr spectra from the tert-butoxy adducts prepared independently from other sources. Accordingly, it seems to be the tert-butylperoxy adduct. Similarly, hydrogen peroxide gave a different spectrum from the hydroxy adducts. Alkyl hydroperoxides caused molecule-induced homolysis with the nitroso compounds to produce alkoxy adducts of the respective nitroso compounds. Some phenyl and duryl alkoxy nitroxides undergo decomposition to give alkyl radicals which were trapped by the nitroso compounds.

scholarly journals Inhibition of Cytochrome P450 (CYP450) Isoforms by Isoniazid: Potent Inhibition of CYP2C19 and CYP3A

2001 ◽  
Vol 45 (2) ◽  
pp. 382-392 ◽  
Author(s):  
Zeruesenay Desta ◽  
Nadia V. Soukhova ◽  
David A. Flockhart
Keyword(s):  
Cytochrome P450 ◽  
Liver Microsomes ◽  
Cost Effective ◽  
Competitive Inhibitor ◽  
Inhibitory Effect ◽  
Significant Inhibition ◽  
Specific Substrate ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
The Mean

ABSTRACT Isoniazid (INH) remains the most safe and cost-effective drug for the treatment and prophylaxis of tuberculosis. The use of INH has increased over the past years, largely as a result of the coepidemic of human immunodeficiency virus infection. It is frequently given chronically to critically ill patients who are coprescribed multiple medications. The ability of INH to elevate the concentrations in plasma and/or toxicity of coadministered drugs, including those of narrow therapeutic range (e.g., phenytoin), has been documented in humans, but the mechanisms involved are not well understood. Using human liver microsomes (HLMs), we tested the inhibitory effect of INH on the activity of common drug-metabolizing human cytochrome P450 (CYP450) isoforms using isoform-specific substrate probe reactions. Incubation experiments were performed at a single concentration of each substrate probe at its Km value with a range of INH concentrations. CYP2C19 and CYP3A were inhibited potently by INH in a concentration-dependent manner. At 50 μM INH (∼6.86 μg/ml), the activities of these isoforms decreased by ∼40%. INH did not show significant inhibition (<10% at 50 μM) of other isoforms (CYP2C9, CYP1A2, and CYP2D6). To accurately estimate the inhibition constants (Ki values) for each isoform, four concentrations of INH were incubated across a range of five concentrations of specific substrate probes. The meanKi values (± standard deviation) for the inhibition of CYP2C19 by INH in HLMs and recombinant human CYP2C19 were 25.4 ± 6.2 and 13 ± 2.4 μM, respectively. INH showed potent noncompetitive inhibition of CYP3A (Ki = 51.8 ± 2.5 to 75.9 ± 7.8 μM, depending on the substrate used). INH was a weak noncompetitive inhibitor of CYP2E1 (Ki = 110 ± 33 μM) and a competitive inhibitor of CYP2D6 (Ki = 126 ± 23 μM), but the mean Ki values for the inhibition of CYP2C9 and CYP1A2 were above 500 μM. Inhibition of one or both CYP2C19 and CYP3A isoforms is the likely mechanism by which INH slows the elimination of coadministered drugs, including phenytoin, carbamazepine, diazepam, triazolam, and primidone. Slow acetylators of INH may be at greater risk for adverse drug interactions, as the degree of inhibition was concentration dependent. These data provide a rational basis for understanding drug interaction with INH and predict that other drugs metabolized by these two enzymes may also interact.

Electrophysiological derangements induced by lipid peroxidation in cardiac tissue

1987 ◽  
Vol 253 (5) ◽  
pp. H1089-H1097 ◽  
Author(s):  
H. Nakaya ◽  
N. Tohse ◽  
M. Kanno
Keyword(s):  
Lipid Peroxidation ◽  
Guinea Pig ◽  
Cardiac Tissue ◽  
Membrane Lipids ◽  
Cumene Hydroperoxide ◽  
Butylated Hydroxytoluene ◽  
Cardiac Tissues ◽  
Conduction Disturbances ◽  
Tert Butyl Hydroperoxide ◽  
Mda Content

Recently it has been postulated that oxygen-derived free radicals may be involved in reperfusion-induced arrhythmias. This study was undertaken to evaluate cellular electrophysiological alterations produced by peroxidation of membrane lipids in isolated cardiac tissues. In retrogradely perfused guinea pig hearts, perfusion of organic hydroperoxides, cumene hydroperoxide (CH), and tert-butyl hydroperoxide (TBH) caused conduction disturbances and arrhythmias, concomitantly with an increase in malondialdehyde (MDA) content of the myocardium. The hydroperoxides decreased the maximum diastolic potential, action potential amplitude, and maximum upstroke velocity of phase 0 in both canine Purkinje fibers and guinea pig papillary muscles. They also induced abnormal automaticity, such as depolarization-induced automaticity, delayed afterdepolarizations, and triggered activity. Mechanical abnormalities including increased resting tension and aftercontractions, presumably resulting from intracellular Ca2+ overload, were produced by the hydroperoxides. Pretreatment with butylated hydroxytoluene, an antioxidant, significantly inhibited the hydroperoxide-induced electrophysiological derangements and MDA accumulation in the myocardium. These results suggest that lipid peroxidation of membranes causes various electrophysiological and mechanical abnormalities and may play a role in the genesis of reperfusion-induced arrhythmias.

Caffeine-derived N-nitroso compounds IV: kinetics of mononitrosocaffeidine demethylation by rat liver microsomes

1994 ◽  
Vol 79 (1) ◽  
pp. 117-122 ◽  
Author(s):  
Renu Razdan ◽  
Eva Frei ◽  
Bertold Spiegelhalder ◽  
Maqsood Siddiqi
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
Nitroso Compounds ◽  
Rat Liver Microsomes ◽  
Kinetics Of

Spin adduct formation from lipophilic EMPO-derived spin traps with various oxygen- and carbon-centered radicals

2005 ◽  
Vol 69 (2) ◽  
pp. 297-305 ◽  
Author(s):  
Klaus Stolze ◽  
Natascha Udilova ◽  
Thomas Rosenau ◽  
Andreas Hofinger ◽  
Hans Nohl
Keyword(s):  
Adduct Formation ◽  
Spin Adduct ◽  
Spin Traps

Promoters for the Reaction of Rubber with Carbon Black

1955 ◽  
Vol 28 (3) ◽  
pp. 895-905 ◽  
Author(s):  
Kenneth W. Doak ◽  
George H. Ganzhorn ◽  
Bernard C. Barton
Keyword(s):  
Tensile Strength ◽  
Carbon Black ◽  
Cumene Hydroperoxide ◽  
Butyl Rubber ◽  
Nitroso Compounds ◽  
Active Centers ◽  
Alkyl Radicals ◽  
Styrene Copolymers ◽  
Aromatic Nitroso Compounds ◽  
Butadiene Styrene

Abstract Heating unvulcanized mixtures of rubber and carbon black gives increased electrical resistivity, reduced hysteresis and hardness, higher modulus, and increased abrasion resistance to the vulcanizate. This is believed to result from improved dispersion of carbon black, accompanying a chemical reaction between rubber and carbon black. Butyl rubber, with low unsaturation, reacts more slowly than Hevea rubber or butadiene-styrene copolymers (GR-S). Chemical promoters decrease the time and temperature required for the reaction. Certain quinones and aromatic nitroso compounds are effective in both Hevea and Butyl rubber. t-Butyl perbenzoate and cumene hydroperoxide are particularly effective in Hevea rubber and GR-S containing channel black, and when used in optimum amounts, do not adversely affect tensile strength. Hexachlorocyclopentadiene and hexachlorophenol are effective in both Hevea and Butyl rubber, l,3-Dichloro-5,5-dimethylhydantoin and hexachlorocyclopentadiene are effective in Butyl containing channel or furnace blacks. Chemical promoters are believed to initiate allylic or alkyl radicals on rubber chains, which react with active centers on carbon black, forming primary valence bonds.

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