At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...

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Free Radicals in the Physiological Control of Cell Function

Reactive oxygen species and antioxidant machinery in abiotic stress tolerance in crop plants

Publisher Summary This chapter discusses the role of free radicals and catalytic metal ions in human disease. The importance of transition metal ions in mediating oxidant damage naturally leads to the question as to what forms of such ions might be available to catalyze radical reactions in vivo . The chapter discusses the metabolism of transition metals, such as iron and copper. It also discusses the chelation therapy that is an approach to site-specific antioxidant protection. The detection and measurement of lipid peroxidation is the evidence most frequently cited to support the involvement of free radical reactions in toxicology and in human disease. A wide range of techniques is available to measure the rate of this process, but none is applicable to all circumstances. The two most popular are the measurement of diene conjugation and the thiobarbituric acid (TBA) test, but they are both subject to pitfalls, especially when applied to human samples. The chapter also discusses the essential principles of the peroxidation process. When discussing lipid peroxidation, it is essential to use clear terminology for the sequence of events involved; an imprecise use of terms such as initiation has caused considerable confusion in the literature. In a completely peroxide-free lipid system, first chain initiation of a peroxidation sequence in a membrane or polyunsaturated fatty acid refers to the attack of any species that has sufficient reactivity to abstract a hydrogen atom from a methylene group.

Role of free radicals and catalytic metal ions in human disease: an overview.

Fish bioaccumulation and biomarkers in environmental risk assessment: a review

The role of lipid peroxidation and antioxidants in oxidative modification of LDL.

This laboratory has previously postulated that bromobenzene-induced hepatic necrosis results from the formation of a reactive metabolite that arylates vital cellular macromolecules. Accordingly, the severity of liver necrosis has been compared with the formation of metabolites of bromobenzene and with covalent binding of metabolites in vivo and in vitro after various pretreatment regimens that alter hepatotoxicity. These data provide direct kinetic evidence that 3,4-bromobenzene oxide is the reactive hepatotoxic metabolite. The studies also demonstrate that the hepatotoxic metabolite is preferentially conjugated (detoxified) with glutathione, thereby depleting glutathione from the liver. Liver necrosis and arylation of cellular macromolecules occur only when glutathione is no longer available. Thus, a dose threshold exists for bromobenzene-induced hepatic necrosis.

Bromobenzene-Induced Liver Necrosis. Protective Role of Glutathione and Evidence for 3,4-Bromobenzene Oxide as the Hepatotoxic Metabolite

The possibility that glutathione may protect against acetaminophen-induced hepatic necrosis was examined. Pretreatment of mice with diethyl maleate, which depletes hepatic glutathione, potentiated acetaminophen-induced hepatic necrosis, whereas pretreatment with cysteine, a glutathione precursor, prevented hepatic damage. Administration of acetaminophen caused a dose-dependent depletion of hepatic glutathione. Glutathione depletion by acetaminophen was enhanced by treatments that potentiate the hepatic necrosis and covalent binding produced by the toxic metabolite of acetaminophen. Conversely, glutathione depletion was inhibited by treatments that protect against these toxic effects. Moreover, covalent binding of this metabolite to hepatic macromolecules did not occur until the availability of glutathione was exhausted through conjugation with the metabolite. Similarly, alteration of glutathione availability by pretreatment with diethyl maleate or cysteine, respectively, increased or decreased covalent binding of the toxic metabolite. We propose that. a fundamental role of glutathione in the body may be to protect tissues against electrophilic attack by drug metabolites and other alkylating agents.

Acetaminophen-induced hepatic necrosis. iv. protective role of glutathione

A number of recent reports indicate that massive overdoses of acetaminophen can produce a fulminant hepatic necrosis in man. Acetaminophen-induced hepatic necrosis thereforne was examised in experimental animals. Centrilobular hepatic necrosis similar to that seen in man was shown to be dose dependent in mice and rats. To determine whether acetaminophen-induced hepatotoxicity was mediated throug an active metabolite, acetaminophen concentrations in rat and mouse tissues were compared with the severity of liver damage after alteration of the rate of metabolism of acetaminophen. Phenobarbital pretreatment stimulated the disappearance of acetaminophen from tissues but markedly potentiated the hepatic necrosis. In contrast, piperonyl butoxide pretreatment inhibited the metabolism and disappearance of acetaminophen from tissues yet dramatically protected against hepatic necrosis. Additional studies demonstrated that pretreatment with 3-methylcholanthrene also potentiated acetaminophen-induced hepatic necrosis whereas cobaltous chloride, which inhibits synthesis of cytochrome P-450, prevented the hepatic damage. We propose that acetaminophen-induced hepatic necrosis is mediated by a toxic metabolite of acetaminophen.

Acetaminophen-induced hepatic necrosis. i. role of drug metabolism

The relationship between the metabolic disposition of acetaminophen and the susceptibility of hamsters, mice and rats to acetaminophen-induced liver necrosis has been examined. The fraction of low dos

Acetaminophen-induced hepatic necrosis. VI. Metabolic disposition of toxic and nontoxic doses of acetaminophen.

Doses of 3H-acetaminophen (300-750 mg/kg) that cause necrosis in mice were shown to result in large amounts of radiolabeled material covalently bound to mouse liver protein in vivo (2 nmol/mg of protein or approximately one molecule bound per two molecules of protein in microsomes and cytoplasm). Both covalent binding and hepatic necrosis were dose dependent, and the peak level of binding preceded the development of recognizable necrosis by at least one to two hours. Pretreatment of mice with phenobarbital, piperonyl butoxide or cobaltous chloride, which changed the rate of metabolism of 3H-acetaminophen and altered the severity of hepatic necrosis, similarly affected the extent of hepatic binding of radiolabeled metabolite. Furthermore, the degree of binding in individual mice was always directly proportional to the severity of hepatic necrosis regardless of the biologic variation among various animals. Accordingly, we propose that acetaminophen-induced hepatic necrosis may be caused by the covalent binding of a chemically reactive metabolite to vital hepatsic macromolecules.

Jerry R. Mitchell

Papers

Bromobenzene-Induced Liver Necrosis. Protective Role of Glutathione and Evidence for 3,4-Bromobenzene Oxide as the Hepatotoxic Metabolite

Acetaminophen-induced hepatic necrosis. iv. protective role of glutathione

Acetaminophen-induced hepatic necrosis. i. role of drug metabolism

Acetaminophen-induced hepatic necrosis. VI. Metabolic disposition of toxic and nontoxic doses of acetaminophen.

Acetaminophen-induced hepatic necrosis. ii. role of covalent binding in vivo