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Cytochrome reactive species

Thus, superoxide itself is obviously too inert to be a direct initiator of lipid peroxidation. However, it may be converted into some reactive species in superoxide-dependent oxidative processes. It has been suggested that superoxide can initiate lipid peroxidation by reducing ferric into ferrous iron, which is able to catalyze the formation of free hydroxyl radicals via the Fenton reaction. The possibility of hydroxyl-initiated lipid peroxidation was considered in earlier studies. For example, Lai and Piette [8] identified hydroxyl radicals in NADPH-dependent microsomal lipid peroxidation by EPR spectroscopy using the spin-trapping agents DMPO and phenyl-tcrt-butylnitrone. They proposed that hydroxyl radicals are generated by the Fenton reaction between ferrous ions and hydrogen peroxide formed by the dismutation of superoxide. Later on, the formation of hydroxyl radicals was shown in the oxidation of NADPH catalyzed by microsomal NADPH-cytochrome P-450 reductase [9,10]. [Pg.774]

A less common reactive species is the Fe peroxo anion expected from two-electron reduction of O2 at a hemoprotein iron atom (Fig. 14, structure A). Protonation of this intermediate would yield the Fe —OOH precursor (Fig. 14, structure B) of the ferryl species. However, it is now clear that the Fe peroxo anion can directly react as a nucleophile with highly electrophilic substrates such as aldehydes. Addition of the peroxo anion to the aldehyde, followed by homolytic scission of the dioxygen bond, is now accepted as the mechanism for the carbon-carbon bond cleavage reactions catalyzed by several cytochrome P450 enzymes, including aromatase, lanosterol 14-demethylase, and sterol 17-lyase (133). A similar nucleophilic addition of the Fe peroxo anion to a carbon-nitrogen double bond has been invoked in the mechanism of the nitric oxide synthases (133). [Pg.397]

Various defense mechanisms have evolved to protect humans and other animals from the thousands of chemicals present in food, drinks, and the environment. Of particular interest are cytochrome P450 (CYP) enzymes, which catalyze the final step in the incorporation of oxygen into organic molecules. They frequently convert xenobi-otics, including human-made chemicals and drugs, into less toxic products but can also transform nontoxic chemicals into toxic or carcinogenic-reactive species. [Pg.386]

The effects of chromium(III) chloride and sodium chromate(VI) on the hepatotoxicity of carbon tetrachloride exposure to mouse hepatocytes were examined by Tezuka et al. (1995). Primary cultures of mouse hepatocytes were pretreated with 10 or 100 pM chromium for 24 hours followed by exposure to 1-5 mM carbon tetrachloride for up to 1 hour. Chromium(VI) pretreatment significantly reduced the cell toxicity as well as lipid peroxidation caused by carbon tetrachloride. Chromium(III) pretreatment did not have any effect on cell toxicity. About 50% of chromium(VI) was taken up and reduced in the cells by 90% to chromium(III) within 10 minutes. The initial uptake rate of chromium(HI) into cells was greater than 500-fold less than chromium(VI), and only about 5% was absorbed. The protection against carbon tetrachloride damage by chromium(VI) was attributed to its rapid uptake and conversion to chromium(III), and it was determined that chromium(III) acts as a radical scavenger for the free radicals generated by carbon tetrachloride within the cell. Furthermore, chromium(VI) pretreatment reduced the activity of NADPH cytochrome c reductase which metabolizes carbon tetrachloride to reactive species. [Pg.271]

Pulse Radiolysis A technique related to flash photolysis pulse radiolysis uses very short (nanosecond) intense pulses of ionizing radiation to generate transient high concentrations of reactive species. See Salmon, G. A. and Sykes, A.G., Pulse radiolysis, Methods Enzymol. 227, 522-534, 1993 Maleknia, S.D., Kieselar, J.G., and Downard, K.M., Hydroxyl radical probe of the surface of lysozyme by synchrotron radiolysis and mass spectrometry. Rapid Commun. Mass Spectrom. 16, 53-61, 2002 Nakuna, B.N., Sun, G., and Anderson, V.E., Hydroxyl radical oxidation of cytochrome c by aerobic radiolysis, Free Radic. Biol. Med. 37, 1203-1213, 2004 BataiUe, C., Baldacchino, G., Cosson, R.P. et al., Effect of pressure on pulse radiolysis reduction of proteins, Biochim. Biophys. Acta 1724, 432-439, 2005. [Pg.189]

Figure 27.45. Aflatoxin Reaction. The compound, produced by molds that grow on peanuts, is activated by cytochrome P450 to form a highly reactive species that modifies bases such as guanine in DNA, leading to mutations. Figure 27.45. Aflatoxin Reaction. The compound, produced by molds that grow on peanuts, is activated by cytochrome P450 to form a highly reactive species that modifies bases such as guanine in DNA, leading to mutations.
Superoxide generated by xanthine oxidase or in the redox cycling of paraquat can cause the reductive release of F3 from ferritin, a process that is dependent on the activity of microsomal NADPH-cytochrome P-450 reductase [119]. Iron appears to be an essential component in the formation of reactive species such as superoxide and hydroxyl radical via redox cycling of cephaloridine. Addition of EDTA or of the specific iron chelator desferrioxamine to an incubation system containing renal cortex microsomes and cephaloridine depressed cephaloridine-induced peroxidation of microsomal lipids significantly EDTA showed a weaker effect than desferrioxamine at equimolar concentrations. By chelating F3 preferentially [120], desferrioxamine reduced the availability of F2 produced by the iron redox cycle and decreased cephaloridine-stimu-lated peroxidation of membrane lipids [36, 37]. [Pg.308]

Occasionally, the cytochrome P-450 system converts some chemieals to reactive species with carcinogenic potential (e.g., polycyclic hydrocarbons). The hepatic microsomal cytochrome P-450 system is inducible by many of its substrates. The cytoehrome P-450 of adrenal cortical mitochondria is involved in steroid hydroxylase reactions, and this system contains iron-sulfur (Fc2S2) proteins. [Pg.274]

Carbenes constitute a further class of neutral reactive species that provide a route to alkylation of the prosthetic heme group. The oxidation of sydnones by cytochrome P-450, which yields an alkyl diazonium product, results in inactivation of the enzyme (Ortiz de Montellano and Grab, 1986 Grab et al., 1988). This loss of activity is associated with the formation of (V-alkyl heme adducts best rationalized by addition of a catalytically generated carbene or carbene equivalent to the heme group (Fig. 32). Model studies have shown that diazo compounds do react with reduced iron porphyrins to give N-alkylated products (Komives et al., 1988). The details of the enzymic N-alkylation reactions remain to be defined, but evidence exists for two distinct reaction pathways. The first is... [Pg.249]

The cytochrome P-450-catalyzed oxidation of sulfhydryl, thiocarbonyl, or thiophosphate groups produces reactive species that, in some instances, inactivate the enzyme in a true mechanism-based process. The oxidation of parathion. [Pg.251]

Assays carried out in human and in rat liver microsomes by some olive oil phenols demonstrated inhibition of cytochrome P450 activity, specifically of CYP3A and CYP2C11 markers and of reactive species generation. [Pg.884]

Cytochrome P-450 hydroxylate many compounds. These include the hydroxylations of steroid hormone synthesis and the hydroxylation of thousands of xenobiotics (foreign compounds), including drugs such as phenobarbital and environmental carcinogens such as benzpyrene, a constituent of the smoke from tobacco and backyard grills. Hydroxylation of foreign substances usually increases their solubility and is a step in their detoxification, or metabolism and excretion. In some cases, however, some of these reactions activate potentially carcinogenic substances to more reactive species. Aflatoxin B, for example, is converted to a more reactive species either by hydroxylation or epoxidation. [Pg.1280]


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