The mechanism of reductive dehalogenation of halothane by liver cytochrome P450

Ahr, H J; King, Laurence J.; Nastainczyk, Wolfgang; Ullrich, Volker

doi:10.1016/0006-2952(82)90186-1

Cited by 129 publications

(54 citation statements)

References 20 publications

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“…The competition between these reactions could also be at the origin of the different levels of cytochrome P450-Fe(II1)-R complexes observed as a function of R. Such radicals R' have also been detected and invoked to explain cytochrome P450 destruction upon metabolic oxidation of Only very few cytochrome P450 complexes involving a a-iron-carbon bond have been previously reported in the literature. All of them derive from the reduction of the halogenated compounds, halothane CF3CHCIBr [29] or benzyl halides ArCHzX [28], in anaerobic conditions (Scheme 7). The above-described cytochrome P450 complexes, characterized by Soret peaks around 480 nm, would thus be the first o-cytochrome P450-Fe(III)-R complexes formed upon the oxidation of a substrate.…”

Section: Nature Of' the Cytochrome P450 Complexes Exhibiting A Soret mentioning

confidence: 99%

Reaction of Monosubstituted Hydrazines and Diazenes with Rat‐Liver Cytochrome P450

Battioni

Mahy

Delaforge

et al. 1983

European Journal of Biochemistry

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The alkyldiazenes RN = NH (R = CH3 or CzHs) react with reduced microsomal cytochrome P450 leading to complexes exhibiting a Soret peak at 446 nm. Upon oxidation of the [cytochrome P450-Fe(II)(CH3N = NH)] complex with limited amounts of dioxygen, a new complex characterized by a Soret peak at 486 nm is formed. The latter complex was also formed upon slow reaction of methyldiazene with microsomal cytochrome P450-Fe(III) or in situ oxidation of methylhydrazine by limited amounts of O2 or ferricyanide. This complex is rapidly destroyed by 0 2 or ferricyanide in excess and more slowly by excess dithionite in the presence of CO.Reactions of ethyldiazene or benzyldiazene with cytochrome P450-Fe(I 11) afforded similar complexes characterized by Soret peaks around 480 nm.These results, when compared to those recently described on reactions of monosubstituted hydrazines RNHNH2 and diazenes R N = N H with hemoglobin and iron-porphyrins, are consistent with a [cytochrome P450-Fe(II)(RN = NH)] structure for the 446-nm-absorbing complexes and a a-alkyl cytochrome P450-Fe(III)-R structure for the complexes characterized by a Soret peak around 480 nm. They also suggest a a-cytochrome P450-Fe(III)-Ph structure for the complex derived from phenylhydrazine oxidation, recently described in the literature. Finally, they provide the first evidence that cytochrome P450-Fe(III)-R complexes are formed upon microsomal oxidation of alkyl or phenylhydrazines. PFe"The dioxygen-dependent oxidation of monosubstituted hydrazines in the presence of iron-porphyrins has been recently studied [I51 and the successive formation of two ironligand complexes in the reaction has been established (Scheme 1). The first complex derives from the binding of the diazene RN = NH, the two-electron oxidation product of the starting hydrazine RNHNH2, to the iron(I1)-porphyrin. The second complex is the o-alkyl (or a-aryl) porphyriniron(II1)-R complex which is formed by a one-electron oxidation of the didzene-iron(1I) complex. The iron(II1)-methyl

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Section: Nature Of' the Cytochrome P450 Complexes Exhibiting A Soret mentioning

confidence: 99%

Reaction of Monosubstituted Hydrazines and Diazenes with Rat‐Liver Cytochrome P450

Battioni

Mahy

Delaforge

et al. 1983

European Journal of Biochemistry

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“…The enzymes catalyze a broad range of reactions such as hydroxylation [5], decarboxylation [6], epoxidation [7], reductive dehalogenation [8], amine/oxygen dealkylation [9], and sulfoxidation [10], employing molecular oxygen and electrons [e.g. from NAD(P)H].…”

Section: Introductionmentioning

confidence: 99%

Regioselective Biocatalytic Hydroxylation of Fatty Acids by Cytochrome P450s

2017

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“…Carbon tetrachloride (CCl 4 ) has been used to induce necrosis in control experiments for studies on apoptosis [26][27][28][29] and is one of most typical model agents for studying the pathogenesis of liver injury. The hepatotoxicity of CCl 4 in vivo has been well studied, indicating the importance of the reductive dehalogenation of CCl 4 catalyzed by cytochrome P450 in the endoplasmic reticulum (ER) as the initial event of the toxic cascades, [30][31][32][33][34] and it is widely accepted that CCl 4 causes hepatic centrilobular necrosis.…”

Section: Introductionmentioning

confidence: 99%

Zonal necrosis prevented by transduction of the artificial anti-death FNK protein

et al. 2005

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Protection of cells from necrosis would be important for many medical applications. Here, we show protein transduction domain (PTD)-FNK therapeutics based on protein transduction to prevent necrosis and acute hepatic injury with zonal death induced by carbon tetrachloride (CCl 4 ). PTD-FNK is a fusion protein comprising the HIV/Tat PTD and FNK, a gain-offunction mutant of anti-apoptotic Bcl-x L . PTD-FNK protected hepatoma HepG2 from necrotic death induced by CCl 4 , and additionally, increased the apoptotic population among cells treated with CCl 4 . A concomitant treatment with a pancaspase inhibitor Z-VAD-FMK (N-benzyloxycarbonyl-Val-AlaAsp-fluoromethylketone), which alone could not prevent the necrosis, protected these cells from the apoptosis. When preinjected intraperitoneally, PTD-FNK markedly reduced zonal liver necrosis caused by CCl 4 . Moreover, injection of PTD-FNK accompanied by Z-VAD-FMK suppressed necrotic injury even after CCl 4 administration. These results suggest that PTD-FNK has great potential for clinical applications to prevent cell death, whether from apoptosis or necrosis, and organ failure.

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The mechanism of reductive dehalogenation of halothane by liver cytochrome P450

Cited by 129 publications

References 20 publications

Reaction of Monosubstituted Hydrazines and Diazenes with Rat‐Liver Cytochrome P450

Reaction of Monosubstituted Hydrazines and Diazenes with Rat‐Liver Cytochrome P450

Regioselective Biocatalytic Hydroxylation of Fatty Acids by Cytochrome P450s

Zonal necrosis prevented by transduction of the artificial anti-death FNK protein

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