Chemical Mechanisms in Carbon Tetrachloride Toxicity

Recknagel, Richard O.; Glende, Eric A.; Hruszkewycz, Andrew M.

doi:10.1016/b978-0-12-566503-2.50010-0

Cited by 113 publications

(57 citation statements)

References 78 publications

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“…For example, attempts to detect the formation of a free-radical product resulting from instance with polymorphonuclear leucocytes (Rosen & Klebanoff, 1979;Green et al, 1979) and with isolated hepatocytes (Tomasi et al, 1980). Carbon tetrachloride is a much studied hepatotoxin (Recknagel, 1967;Slater, 1972;Recknagel et al, 1977;Dianzani, 1982) that produces centrilobular necrosis and fatty degeneration of the liver. CC14 is actively metabolized by isolated hepatocytes, and this metabolic activation is associated with an increased lipid peroxidation (Poli et al, 1978) and with decreases in protein synthesis and in lipoprotein secretion (Poli et al, 1979).…”

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“…CC14 is actively metabolized by isolated hepatocytes, and this metabolic activation is associated with an increased lipid peroxidation (Poli et al, 1978) and with decreases in protein synthesis and in lipoprotein secretion (Poli et al, 1979). The activated intermediate resulting from the metabolism of CC14 by the NADPH-cytochrome P-450 electron-transport chain in liver endoplasmic reticulum is generally considered to be the trichloromethyl free radical CC13 (Slater, 1972;Recknagel et al, 1977;. Previous attempts to trap the CC13 free radical with 2-methyl-2-nitrosopropane in liver microsomal suspensions (Ingall et al, 1978) were not successful, but more recently Poyer et al (1980) and Tomasi et al (1980) have reported the successful trapping of CC13 in liver microsomal fractions (referred to below simply as 'microsomes') with the spin trap N-benzylidene-2-methylpropylamine N-oxide (PBN).…”

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Spin-trapping studies on the free-radical products formed by metabolic activation of carbon tetrachloride in rat liver microsomal fractions isolated hepatocytes and in vivo in the rat

Albano¹,

Lott²,

Slater³

et al. 1982

Biochemical Journal

167

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1. The metabolic activation of carbon tetrachloride to free-radical intermediates is an important step in the sequence of disturbances leading to the acute liver injury produced by this toxic agent. Electron-spin-resonance (e.s.r.) spin-trapping techniques were used to characterize the free-radical species involved. 2. Spin trapping was applied to the activation of carbon tetrachloride by liver microsomal fractions in the presence of NADPH, and by isolated intact rat hepatocytes. The results obtained with the spin trap N-benzylidene-2-methylpropylamine N-oxide ('phenyl t-butyl nitrone') (PBN) and [13Clcarbon tetrachloride provide unequivocal evidence for the formation and trapping of the trichloromethyl free radical in these systems. 3. With the spin trap 2-methyl-2-nitrosopropane, however, the major free-radical species trapped are unsaturated lipid radicals produced by the initiating reaction of lipid peroxidation. 4. Although pulse radiolysis and other evidence support the very rapid formation of the trichloromethyl peroxy radical from the trichloromethyl radical and oxygen, no clear evidence for the trapping of the peroxy radical was obtainable. 5. The effects of a number of free-radical scavengers and metabolic inhibitors on the formation of the PBN-trichloromethyl radical adduct were studied, as were the influences of changing the concentration of PBN and incubation time. 6. High concentrations of the spin traps used were found to have significant effects on cytochrome P-450-mediated reactions; this requires caution in interpreting results of experiments done in the presence of PBN at concentrations greater than 50mM.

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confidence: 99%

Spin-trapping studies on the free-radical products formed by metabolic activation of carbon tetrachloride in rat liver microsomal fractions isolated hepatocytes and in vivo in the rat

Albano¹,

Lott²,

Slater³

et al. 1982

Biochemical Journal

167

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“…Thus, the temporal sequence of changes, Mb oxidation, loss of functional morphology and finally loss of membranal integrity, indicates that Mb oxidation may be an early indicator of oxidative (peroxidative) injury in heart cells. Many previous studies of peroxidative injury have focussed on the derangement of membrane lipids which occurs as a result of a free-radical process [26]. Howeve, major changes in membrane permeability do not occur until substantial destruction of membrane lipids occurs and, therefore, the site of lethal injury may be specific proteins with critical functional groups which are particularly sensitive to peroxides or other reactive species generated during peroxidative processes [27].…”

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confidence: 99%

Oxidation of myoglobin in isolated adult rat cardiac myocytes by 15‐hydroperoxy‐5,8,11,13‐eicosatetraenoic acid

1983

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The oxidation of intracellular myoglobin by 15‐hydroperoxy‐5,8,11,13‐eicosatetraenoic acid was studied in suspensions of isolated adult rat heart cells. Myoglobin was converted to a species identified as ferrylMb by its reaction with Na2S to form ferrous sulfmyoglobin. This process was time‐dependent and concentration‐dependent in a manner consistent with direct accessibility of the exogenous peroxide to the cytosolic protein. The results indicate that myoglobin oxidation may be an early sign of oxidative injury and may limit myocardial function by elimination of this short‐term O2 reserve.

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“…Lipid peroxidation occurs when free radicals oxidize and damage the lipid bilayer of cell membranes. The ferrous -ferric ion pair provided by iron within the porphyrin ring in myoglobin catalyzes this process and facilitates widespread lipid peroxidation in muscle tissue [44]. Cell membrane degradation impairs the normal permeability of the cell and results in further cellular edema, Ca ++ influx, and Na + influx.…”

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confidence: 99%

Crush injury and rhabdomyolysis

Malinoski

Slater

Mullins

2004

Critical Care Clinics

212

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Although clinical syndromes consistent with rhabdomyolysis were recognized in the late 19th and early 20th centuries, the modern history of the crush syndrome begins with Bywaters' and Beal's classic description of the entrapped bombing victims of London during World War II [1 -4]. They reported five cases of crush injury, in which victims had one or more of their extremities trapped under debris for prolonged periods of time. All five patients presented in shock, had swollen extremities, developed dark urine, progressed to renal failure, and eventually died. Histologic examination of the kidney revealed tubular necrosis and pigmented casts. In 1944, Bywaters and Stead identified myoglobin as the urinary pigment and proposed its role in the development of renal failure [5].Large numbers of patients with crush injuries and rhabdomyolysis have been reported after the collapse of mines [6,7], severe beatings [8], and earthquakes [9 -15]. In the United States, alcohol intoxication associated with prolonged muscle compression and seizures is the most common etiology of rhabdomyolysis [16]. Serum creatine kinase (CK) levels correlate with the degree of muscle injury [14] and can be used to assess the severity of rhabdomyolysis. Acute renal failure (ARF) is one of the most serious consequences of rhabdomyolysis and occurs in 4% to 33% of cases, carrying with it a mortality rate of 3% to 50% [17]. Rhabdomyolysis accounts for 5% to 7% of all cases of ARF in the United States [18].This article focuses on the pathophysiology and treatment of myoglobinuric renal failure caused by traumatic rhabdomyolysis and crush injuries.

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Chemical Mechanisms in Carbon Tetrachloride Toxicity

Cited by 113 publications

References 78 publications

Spin-trapping studies on the free-radical products formed by metabolic activation of carbon tetrachloride in rat liver microsomal fractions isolated hepatocytes and in vivo in the rat

Spin-trapping studies on the free-radical products formed by metabolic activation of carbon tetrachloride in rat liver microsomal fractions isolated hepatocytes and in vivo in the rat

Oxidation of myoglobin in isolated adult rat cardiac myocytes by 15‐hydroperoxy‐5,8,11,13‐eicosatetraenoic acid

Crush injury and rhabdomyolysis

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