The mechanism of chloroform and carbon monoxide formation from carbon tetrachloride by microsomal cytochrome P-450

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

doi:10.1016/0006-2952(80)90022-2

Cited by 122 publications

(60 citation statements)

References 15 publications

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“…In addition, the existence of a reactive dichlorocarbene has been proposed (5) on the basis of spectral studies of complex formation between halocarbon metabolites and cytochrome P-450. The observed formation ofcarbon monoxide from carbon tetrachloride is in accord with two successive one-electron reductions catalyzed by cytochrome P-450 (9).…”

supporting

confidence: 65%

Reductive metabolism of carbon tetrachloride by human cytochromes P-450 reconstituted in phospholipid vesicles: mass spectral identification of trichloromethyl radical bound to dioleoyl phosphatidylcholine.

Trudell¹,

Bösterling²,

Trevor³

1982

Proc. Natl. Acad. Sci. U.S.A.

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It has been proposed that covalent binding of reactive metabolites to liver membrane constituents may be responsible for the hepatoxicity ofcarbon tetrachloride. This study demonstrates that trichloromethyl free radical is the major reductive metabolite of carbon tetrachloride by cytochrome P-450 and that this free radical is capable ofbinding to double bonds of fatty acyl chains of the phospholipids in the membrane surrounding cytochrome P-450. The structural identification of the reactive free radical metabolite and the product of its addition to phospholipids was accomplished by use of a reconstituted system of human cytochromes P-450, NADPH-cytochrome P-450 reductase, and cytochrome b5 in phospholipid vesicles. The reconstituted vesicles contained a mixture of dioleoyl phosphatidylcholine and egg phosphatidylethanolamine that served as both structural components and targets for trichloromethyl free radical binding. After incubation of these vesicles under a N2 atmosphere in the presence of NADPH with '4CC14, the phospholipids were extracted and then separated by high-pressure liquid chromatography. The dioleoyl phosphatidylcholine fraction was transesterified and the resulting single "4C-labeled fatty acid methyl ester was purified by reversephase chromatography. Desorption chemical ionization mass spectrometry with ammonia as reagent gas as well as desorption electron-impact mass spectrometry permitted identification of the molecular structure as a mixture of 9-and 1O-(trichloromethyl)stearate methyl esters.

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supporting

confidence: 65%

Reductive metabolism of carbon tetrachloride by human cytochromes P-450 reconstituted in phospholipid vesicles: mass spectral identification of trichloromethyl radical bound to dioleoyl phosphatidylcholine.

Trudell¹,

Bösterling²,

Trevor³

1982

Proc. Natl. Acad. Sci. U.S.A.

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“…The primary step in CC14 metabolism is reductive and consists of transfer of an electron to CC14 by the P-450 system yielding CC13* (18). There is also evidence for a two-electron reduction yielding dichlorocarbene, but this step seems to be quantitatively minor (19). These reductive steps are carried out by P-450.…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Rifampicin against Acute Liver Injury Induced by Carbon Tetrachloride in Mice

Huang

Okuno

Takasu

et al. 1995

Japanese Journal of Pharmacology

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ABSTRACT-Rifampicin conferred significant protection against carbon tetrachloride (CC14)-induced liver injury. Serum alanine transaminase (ALT) and aspartate transaminase (AST) activities were not markedly altered and only hepatocellular fatty degeneration was found in mice pretreated with rifampicin (200 mg/kg), whereas severe centrilobular necrosis was observed and serum ALT and AST activities were as high as 281 and 271 I.U./1, respectively, in the control group following administration of CC14 (400,ul/kg). The contents and activities of microsomal drug-metabolizing enzymes in rifampicin-pretreated animals were also much higher than those of the controls. CC14-mediated malondialdehyde (MDA) formation was increased in rifampicin-treated liver microsomes, demonstrating that rifampicin was capable of increasing the NADPH-dependent metabolism of CC14 catalyzed by P-450 2E1 to produce free radicals. However, MDA formation was obviously depressed by rifampicin at varying concentrations from 2 to 32 x 10-6 M in an in vitro cytochrome P-450 (P-450) enzyme system. On the other hand, NADPH oxidation in the metabolism of CC14 and aniline hydroxylation were not suppressed in the presence of rifampicin in this systems, suggesting that rifampicin did not influence the biotransformation of CC14 by P-450 2E1 in vitro. Therefore, the protective effect of rifampicin against CC14 hepatotoxicity appeared to result from the direct inhibition of lipid peroxidation generated by CC14-derived free radicals.

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“…The first step in reductive dehalogenation of CC! 4 is thought to involve its reaction with a reduced metalloporphyrin to form a chloromethyl-metalloporphyrin [11,13,16,18]. The latter intermediate is unstable in the presence of thiol compounds [27] and gives rise to CHCi 3 and the reduced metalloporphyrin.…”

Section: Discussionmentioning

confidence: 99%

“…4 is also known in complex eukaryotic systems, e.g. liver fraction [12][13][14][15] and nitrogen-fixing soybean nodules (Stromeyer. unpublished).…”

Section: Introductionmentioning

confidence: 99%

Transformation of tetra- and trichloromethane to CO2 by anaerobic bacteria is a non-enzymic process

Egli¹

1990

FEMS Microbiology Letters

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The mechanism of chloroform and carbon monoxide formation from carbon tetrachloride by microsomal cytochrome P-450

Cited by 122 publications

References 15 publications

Reductive metabolism of carbon tetrachloride by human cytochromes P-450 reconstituted in phospholipid vesicles: mass spectral identification of trichloromethyl radical bound to dioleoyl phosphatidylcholine.

Reductive metabolism of carbon tetrachloride by human cytochromes P-450 reconstituted in phospholipid vesicles: mass spectral identification of trichloromethyl radical bound to dioleoyl phosphatidylcholine.

Protective Effect of Rifampicin against Acute Liver Injury Induced by Carbon Tetrachloride in Mice

Transformation of tetra- and trichloromethane to CO2 by anaerobic bacteria is a non-enzymic process

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