The reductive metabolism of halogenated alkanes by liver microsomal cytochrome P450

Nastainczyk, Wolfgang; Ahr, Hans-Juergen; Ullrich, Volker

doi:10.1016/0006-2952(82)90187-3

Cited by 92 publications

(39 citation statements)

References 26 publications

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“…Previous studies showed that the dehalogenation of carbon tetrachloride, hexachloroethane, halothane, or (␣-bromoisovaleryl)urea occurred in the liver microsomal fraction of mammalian species and that cytochrome P450 was involved in the microsomal dehalogenation (Fujii et al, 1981;Kubic and Anders, 1981;Ahr et al, 1982;Nastainczyk et al, 1982;Oka et al, 1996). Recent experiments have demonstrated that rat liver microsomes can directly transform halothane to dehalogenated metabolites in a reductive reaction involving the formation of a halothane-free radical intermediate (Baker and Van Dyke, 1984).…”

Section: Discussionmentioning

confidence: 99%

Reductive Metabolism ofp,p′-DDT ando,p′-DDT by Rat Liver Cytochrome P450

Kawa

Shimizu²,

Shiraga³

et al. 2002

Drug Metab Dispos

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This paper is available online at http://dmd.aspetjournals.org ABSTRACT:The in vitro metabolism of p,p-DDT [1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane], an important environmental pollutant, was examined in rat liver, focusing on reductive dechlorination. When p,p-DDT was incubated with liver microsomes of rats in the presence of NADPH or NADH, a dechlorinated metabolite, p,p-DDD [1,1-dichloro-2,2-bis(4-chlorophenyl)ethane], was formed under anaerobic conditions together with a dehydrochlorinated metabolite, p,p-DDE [1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene]. p,p-DDE was also formed from p,p-DDD by liver microsomes. The dechlorinating activity was inhibited by carbon monoxide, metyrapone, and SKF 525-A (proadifen hydrochloride), but the dehydrochlorinating activity was unaffected. The reductase activity toward p,p-DDT was induced by the pretreatment of rats with phenobarbital and dexamethasone. The dechlorination was catalyzed enzymatically by recombinant cytochrome P450 2B1, 3A1, 2B6, and 3A4. When p,p-DDT was incubated with liver microsomes of rats in the presence of both a reduced pyridine nucleotide and FMN, p,p-DDD was also formed under anaerobic conditions. In this case, the dechlorinating activity was not abolished when the microsomes were boiled. The reductase activities were inhibited by carbon monoxide. Hematin exhibited reductase activity toward p,p-DDT in the presence of NADH and FMN. The activity of hematin was also supported by FMNH 2 . The reductive dechlorination also seems to proceed nonenzymatically with the reduced flavin, catalyzed by the heme group of cytochrome P450. Similar enzymatic and nonenzymatic reducing activities were observed toward o,p-DDT [1,1,1-trichloro-2,2-bis(2-chlorophenyl-4-chlorophenyl)ethane].

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Section: Discussionmentioning

confidence: 99%

Reductive Metabolism ofp,p′-DDT ando,p′-DDT by Rat Liver Cytochrome P450

Kawa

Shimizu²,

Shiraga³

et al. 2002

Drug Metab Dispos

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“…The ratio between the amount of fluoride anion and the amount of 4-hydroxyaniline detected, was 1.4 f 0.7 for control microsomes, but 3.8 0. 4 for incubations with liver microsomes from dexamethasonepretreated rats. This points to additional dehalogenation mechanisms occurring in incubations with liver microsomes from dexamethasone-treated rats.…”

Section: F-nmr Measurementsmentioning

confidence: 99%

Reaction pathways for biodehalogenation of fluorinated anilines

Rietjens

Tyrakowska

Veeger

et al. 1990

European Journal of Biochemistry

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Pathways for biodehalogenation of fluorinated aniline derivatives were investigated. Microsomal NADPHdependent dehalogenation of fluoroanilines was shown to proceed by three different reaction pathways. The first route appeared to result in monooxygenation at a fluorinated position and release of the fluorine atom as a fluoride anion. The primary additional reaction product formed is the reactive quinoneimine, not the 4-hydroxyaniline. In NADPH-containing microsomal systems with 4-fluoro-substituted anilines, formation of the 4-hydroxyaniline derivative is observed because NADPH chemically reduces this quinoneimine metabolite. A second pathway for dehalogenation proceeds by protein binding of a fluoro-containing (semi)quinoneimine metabolite, the formation of which may result from the mono-oxygenase reaction (pathway 1) and/or from (re)oxidation of a hydroxyaniline metabolite by superoxide anion radicals produced by the microsomal system. This latter reaction pathway becomes more important with increasing number of fluoro-substituents in the fluoroaniline derivative. The higher ratio of fluoride anion formed to 4-hydroxyaniline derivative detected in incubations with liver microsomes from dexamethasone-treated rats, as compared to incubations with liver microsomes from control rats, can in part be explained by the higher production of superoxide anion radicals observed in the dexamethasone systems.The third mechanism was shown to proceed by formation of a hydroxylated metabolite that loses fluoride anion upon exposure to oxygen. The reactive intermediate formed upon oxygen exposure might be the semiquinoneimine which loses its fluorine atom as a fluoride anion upon dimerization or polymerization and/or protein binding. The fluorohydroxyanilines, in which the hydroxyl group is ortho or para with respect to the fluoro substituent, appear especially to be highly unstable and lose fluoride anion in the presence of oxygen.Finally, it is concluded that all three pathways for dehalogenation of fluorinated aniline derivatives are bioactivation pathways. The reactivity of the (semi)quinoneimines formed in these reactions is dependent on their substitution pattern and increases with increasing number of fluoro-substituents. Therefore, bioactivation for a series of fluorinated aniline derivatives, can be expected to vary with the substitution pattern and to increase with increasing number of halogen substituents.The accumulation of halogen-containing aliphatic and aromatic compounds is a major factor adding to environmental pollution. The phenomenon originates from the widespread use of halogen-containing compounds in industry, commerce and medicine and from the relatively high persistence of these chemicals [I, 21. In addition, these halogencontaining compounds may give rise to a variety of toxic effects caused by either the bioaccumulation of poorly metabolized compounds and/or by their biotransformation to reactive intermediates [2]. One of the reactions resulting in formation of reactive intermediates could be dehaloge...

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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 reductive metabolism of halogenated alkanes by liver microsomal cytochrome P450

Cited by 92 publications

References 26 publications

Reductive Metabolism ofp,p′-DDT ando,p′-DDT by Rat Liver Cytochrome P450

Reductive Metabolism ofp,p′-DDT ando,p′-DDT by Rat Liver Cytochrome P450

Reaction pathways for biodehalogenation of fluorinated anilines

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

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