Role of metals in oxygen radical reactions

Aust, Steven D.; Morehouse, Lee A.; Thomas, Craig E.

doi:10.1016/0748-5514(85)90025-x

Cited by 1,080 publications

(404 citation statements)

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“…Normal GI iron absorption is only about 1 mg/day, leaving 9 mg/day residue. Assuming a stool volume of 0.5 liters/day, one would expect fecal iron to be approximately (9 mg Fe)/(0.5 L) × (1 mmole)/(56 mg) = 0.32 mM, a value 10-fold greater than that in most tissues, and more than adequate to promote the superoxide driven Fenton reaction, if the iron is appropriately chelated [33,38].In living tissues levels of "free" or "low molecular weight, chelate" iron, capable of supporting Fenton chemistry, in the plasma or in tissues are low [39, 40], owing to the presence of iron binding proteins such a transferrin and ferritin. Transferrin, in particular, is able to bind iron tightly and in such a way that it does not participate in the superoxide driven Fenton reaction.…”

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confidence: 99%

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Free radicals and the etiology of colon cancer

Babbs

1990

Free Radical Biology and Medicine

311

173

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This hypothesis paper reviews diverse evidence suggesting that intracolonic production of oxygen radicals may play a role in carcinogenesis. The hypothesis began to evolve when the author made the chance discovery that 1/10,000 dilutions of feces generated detectable quantities of highly reactive hydroxyl radicals (HO). The rate of HO formation, detected using DMSO as a molecular probe, was quite remarkable, corresponding to that which would be produced by over 10,000 rads of gamma irradiation per day, absorbed in the periphery of the fecal mass adjacent to the mucosa. The relatively high concentrations of iron in feces, together with the ability of bile pigments to act as iron chelators that support Fenton chemistry, may very well permit efficient HO generation from superoxide and hydrogen peroxide produced by bacterial metabolism. Such free radical generation in feces could provide a missing link in our understanding of the etiology of colon cancer: the oxidation of procarcinogens either by fecal HO, or by secondary peroxyl radicals (ROO) to form active carcinogens or mitogenic tumor promotors. Intracolonic free radical formation may explain the high incidence of cancer in the colon and rectum, compared to other regions of the GI tract, as well as the observed correlations of a higher incidence of colon cancer with red meat in the diet, which increases stool iron, and with excessive fat in the diet, which may increase the fecal content of procarcinogens and bile pigments. OVERVIEW OF THE HYPOTHESIS AND RELEVANT CHEMICAL MECHANISMSMy intention in this hypothesis paper is to present a new hypothesis suggesting how oxygen derived free radicals, generated in fecal material next to colonic epithelium, may play a significant role in the etiology of colon cancer. This hypothesis derives from an earlier conjecture by Graf and Eaton [1], coupled with the serendipitous discovery in our laboratory that highly reactive HO radicals can be produced abundantly by suspensions of feces under aerobic conditions. As do many other hypotheses for the pathogenic effects of oxygen centered free radicals in biologic systems [2][3][4][5][6], this one also invokes the superoxide driven Fenton reaction:In feces a ready biologic source of superoxide is the respiratory activity of bacteria [7][8][9][10], notably E. coli [11], perhaps together with spontaneous autoxidation of ferrous iron chelates that have been previously reduced by metabolites of the anerobic subpopulation of fecal flora. Another intriguing source of colonic superoxide is the lipoxygenase activity of normal or sloughed colonic epithelial cells [12]. The necessary iron is provided from the diet, since only a small fraction of dietary iron is absorbed in upper GI tract [13,14]. Hydroxyl (HO) radicals so formed within the colon could easily trigger a variety of carcinogenic mechanisms. For example, they could participate in aromatic hydroxylation reactions [15,16] to form carcinogenic products [17]; they could abstract hydrogen atoms from indoles to form radicals t...

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“…We wondered, therefore, whether bile pigments would substitute as suitable Fenton-promoting chelators. This issue is important because HO radical production by Fenton chemistry at near neutral pH is highly dependent on the nature of the iron chelator [33,71,72]. Some iron chelates, such as Fe--EDTA 1:1 support Fenton chemistry readily [71].…”

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Free radicals and the etiology of colon cancer

Babbs

1990

Free Radical Biology and Medicine

311

173

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“…It has become increasingly apparent that transition metals such as iron and copper play critical roles in toxicological and pathological phenomena that lead to oxidative cell damage (for review see Aust et al, 1985). To prevent such phenomena, various chelating agents have been employed to minimize the participation of transition metals.…”

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Deferoxamine inhibits methyl mercury-induced increases in reactive oxygen species formation in rat brain

LeBel

Ali

Bondy

1992

Toxicology and Applied Pharmacology

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“…A large sensitivity ratio indicates that a change in the specified rate constant has a meaningful effect on the rate of lipid peroxidation. One critical rate constant for which literature values varied was that for oxygen addition to lipid alkyl radicals, k [5], ranging from 10 7 to about 5 × 10 9 , depending on the type of lipid radical, LH. In our standard model, we selected a conservative value for this rate constant for nonspecific lipids, 9 × 10 6 , based on the work of Uri.…”

Section: Sensitivity Analysismentioning

confidence: 99%

“…[1][2][3][4][5][6] Owing to their high reactivity, most free radicals postulated to attack biologic substrates must exist in vivo in extremely low instantaneous concentrations. The measurement of highly reactive free radicals such as the hydroxyl radical (HO) therefore represents a formidable technical challenge, which is only beginning to be met in quantitatively meaningful ways.…”

Section: Introductionmentioning

confidence: 99%

Simulation of free radical reactions in biology and medicine: A new two-compartment kinetic model of intracellular lipid peroxidation☆

Babbs

Steiner

1990

Free Radical Biology and Medicine

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--To explore mechanisms of free radical reactions leading to intracellular lipid peroxidation in living systems, we developed a computational model of up to 109 simultaneous enzymatic and free radical reactions thought to be involved in the initiation, propagation, and termination of membrane lipid peroxidation. Rate constants for the various reactions were obtained from the published literature. The simulation model included a lipid membrane compartment and an aqueous cytosolic compartment, between which various chemical species were partitioned. Lipid peroxidation was initiated by the iron-catalyzed, superoxide-driven Fenton reaction. A "C"-language computer program implemented numerical solution of the steady-state rate equations for concentrations of nine relevant free radicals. The rate equations were integrated by a modified Euler technique to describe the evolution with time of simulated concentrations of hydrogen peroxide, ferric and ferrous iron, unsaturated lipid, lipid hydroperoxides, superoxide anion, and biological antioxidants, including SOD and catalase. Initial results led to significant insights regarding mechanisms of membrane lipid peroxidation:1.segregation and concentration of lipids within membrane compartments promotes chain propagation; 2.in the absence of antioxidants computed concentrations of lipid hydroperoxides increase linearly about 40 M/min during oxidative stress; 3.lipid peroxidation is critically dependent upon oxygen concentration and the modeled dependence is similar to the experimental function; 4.lipid peroxidation is rapidly quenched by the presence of Vitamin E-like antioxidants, SOD, and catalase; 5.only small (l to 50 M) amounts of "free" iron are required for initiation of lipid peroxidation; 6. substantial lipid peroxidation occurs only when cellular defense mechanisms have been weakened or overcome by prolonged oxidative stress, hence understanding of the balance between free radical generation and antioxidant defense systems is critical to the understanding and control of free radical reactions in biology and medicine.

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Role of metals in oxygen radical reactions

Cited by 1,080 publications

References 237 publications

Free radicals and the etiology of colon cancer

Free radicals and the etiology of colon cancer

Deferoxamine inhibits methyl mercury-induced increases in reactive oxygen species formation in rat brain

Simulation of free radical reactions in biology and medicine: A new two-compartment kinetic model of intracellular lipid peroxidation☆

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