Superoxide metabolic formation

Oxatomide (l- 3- [4-(diphenylmethyl)-l-piperazinyl] propyl)-l,3-dihydro-2H-benzimidazol-2-one) is an antiallergy drug. Akamatsu has reported that oxatomide decreases neutrophil-generated superoxide anion and hydrogen peroxide formation in a dose-dependent manner. The authors hypothesize that the drug is inhibiting NADPH-dependent oxygen metabolism within the neutrophil (Akamatsu et al., 1993). 

FIGURE 32-7 Sources of free radical formation which may contribute to injury during ischemia-reperfusion. Nitric oxide synthase, the mitochondrial electron-transport chain and metabolism of arachidonic acid are among the likely contributors. CaM, calcium/calmodulin FAD, flavin adenine dinucleotide FMN, flavin mononucleotide HtT, tetrahydrobiopterin HETES, hydroxyeicosatetraenoic acids L, lipid alkoxyl radical LOO, lipid peroxyl radical NO, nitric oxide 0 "2, superoxide radical. 

Alcohol-related liver diseases are complex, and ethanol has been shown to interact with a large number of molecular targets. Ethanol can interfere with hepatic lipid metabolism in a number of ways and is known to induce both inflammation and necrosis in the liver. Ethanol increases the formation of superoxide by Kupffer cells thus implicating oxidative stress in ethanol-induced liver disease. Similarly prooxidants (reactive oxygen species) are produced in the hepatocytes by partial reactions in the action of CYP2E1, an ethanol-induced CYP isoform. The formation of protein adducts in the microtubules by acetaldehyde, the metabolic product formed from ethanol by alcohol dehydrogenase, plays a role in the impairment of VLDL secretion associated with ethanol. 

Another means of metabolic activation is the cyclic reduction/oxidation of the parent compound, resulting in high rates of consumption of NADPH and production of superoxide anion. Either the depletion of NADPH and/or the formation of reactive oxygen radicals could lead to cellular injury. 

Since mitochondria are the site of high oxidative metabolism, they are under continual oxidative stress. In fact, it has been estimated that approximately 2 percent of mitochondrial 02 consumption generates ROS. The mitochondrial electron transfer chain is one of the main sources of ROS in aerobic cells, due to electron leakage from energy-transducing sequences leading to the formation of superoxide radicals. 

Bowman PD, Betz AL, Goldstein GW (1982) Primary culture of microvascular endothelial cells from bovine retina selective growth using fibronectin coated substrate and plasma derived serum. In Vitro 18 626-632 Chat M, Bayol-Denizot C, Suleman G et al. (1998) Drug metabolizing enzyme activities and superoxide formation in primary and immortalized rat brain endothelial cells. Life Sci 62 151-163... 

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