Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.11.1.7 (peroxidase)
65,474 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hydrogen peroxide-dependent oxidation of xenobiotics in a crude fraction of human term placental membranes (nuclei, mitochondria and microsomes) was investigated. Guaiacol was employed as a model substrate. The rate of its oxidation was found to be dependent on the concentration of protein, H2O2 and the substrate as well as the pH of the buffer. Several other classical substrates for peroxidases from different sources viz. pyrogallol, benzidine, p-PDA, DMBD, ABTS, TMPD and TMBD and endogenous chemicals such as bilirubin and epinephrine were also found to undergo oxidation. The xenobiotic oxidizing capacity of the membranes was retained by CaCl2 (0.5 M) extract as well as by the partially purified enzyme obtained by affinity (Con A) chromatography. The H2O2-dependent chemical oxidation by the partially purified peroxidase was inhibited by NaN3 and KCN (IC50 values 41 and 23 microM respectively). These results suggest that peroxidase may be a major enzyme in human term placenta capable of oxidation of endogenous chemicals and xenobiotics.
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PMID:Peroxidase: a novel pathway for chemical oxidation in human term placenta. 129 5

The response of mammalian cell lines to chemicals depends, in part, on the exogenous activation system used for the induction of a biological response. This could be attributed to differences in the expression of enzymes involved in xenobiotic metabolism. We have measured the activities of benzo[a]pyrene hydroxylase, dimethylaminoazobenzene N-demethylase, catalase, superoxide dismutase, peroxidase and glutathione-S-transferase in human lymphoblast TK6, mouse lymphoma L5178Y, Chinese hamster ovary (CHO) and lung (V79) and mouse C3H10T1/2 cell lines as well as in primary hepatocytes and S9 preparations of liver from male F344 rats. Nitroreductase was also measured in some of these preparations. Human lymphoblast TK6 and mouse C3H10T1/2 cells had the capacity to metabolize dimethylaminoazobenzene and the latter cell line also metabolized benzo[a]pyrene, indicating the presence of constitutive mono-oxygenase activity. Cytochrome P450 could not be detected spectrophotometrically in the cell lines. Western blot analysis indicated that P450 from the P450IIA family is expressed in C3H10T1/2 cells. Reactivity was also observed with an antibody to P450IA2; however, the identity of this protein remains uncertain. Superoxide dismutase, catalase and peroxidase, which protect cells against oxygen radical damage, were found in all the cell lines and in rat hepatocytes and S9. The human lymphoblast TK6 cell line, however, had the least of each of these three enzymes. Glutathione-S-transferase activity was detected at varying levels in all cell types. Nitroreductase activity was high in S9 and Chinese hamster ovary cells and lower in mouse lymphoma and Chinese hamster V79 cells.
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PMID:Endogenous xenobiotic enzyme levels in mammalian cells. 171 12

Prostaglandin H synthase (PHS) catalyzes the oxidation of arachidonic acid to prostaglandin H2 in reactions which utilize two activities, a cyclooxygenase and a peroxidase. These enzymatic activities generate enzyme- and substrate-derived free radical intermediates which can oxidize xenobiotics to biologically reactive intermediates. As a consequence, in the presence of arachidonic acid or a peroxide source, PHS can bioactivate many chemical carcinogens to their ultimate mutagenic and carcinogenic forms. In general, PHS-dependent bioactivation is most important in extrahepatic tissues with low monooxygenase activity such as the urinary bladder, renal medulla, skin and lung. Mutagenicity assays are useful in the detection of compounds which are converted to genotoxic metabolites during PHS oxidation. In addition, the oxidation of xenobiotics by PHS often form metabolites or adducts to cellular macromolecules which are specific for peroxidase- or peroxyl radical-dependent reactions. These specific metabolites and/or adducts have served as biological markers of xenobiotic bioactivation by PHS in certain tissues. Evidence is presented which supports a role for PHS in the bioactivation of several polycyclic aromatic hydrocarbons and aromatic amines, two classes of carcinogens which induce extrahepatic neoplasia. It should be emphasized that the toxicities induced by PHS-dependent bioactivation of xenobiotics are not limited to carcinogenicity. Examples are given which demonstrate a role for PHS in pulmonary toxicity, teratogenicity, nephrotoxicity and myelotoxicity.
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PMID:Bioactivation of xenobiotics by prostaglandin H synthase. 191 72

The hepatic glutathione (GSH) system and the influences of xenobiotics have been reviewed. Key steps in the regulation of hepatic GSH are GSH biosynthesis, the GSH-peroxidase/reductase cycle, the cystathionine pathway, and the carrier-mediated export processes. Influences of xenobiotics on these different pathways are discussed. Xenobiotics may lead to liver injury after biotransformation to highly reactive electrophilic metabolites (mainly cytochrome P-450 mediated), which easily conjugate with GSH, thus producing GSH depletion. This GSH depletion and probably an additional loss of protein sulfhydryl groups cause a disturbance of the intracellular calcium homeostasis which leads to an irreversible cell injury. The different acinar distribution of cytochromes P-450 and of GSH and GSH-related detoxication pathways points to a greater susceptibility of perivenous hepatocytes to xenobiotic-induced damage. Also, the intracellular compartmentation of GSH is important for the understanding of hepatocellular injury induced by several xenobiotics.
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PMID:The hepatic glutathione system--influences of xenobiotics. 219 11

To determine whether P450IIE1, a microsomal P450 enzyme inducible by ethanol in the liver, is also present and inducible in the alimentary tract, corresponding frozen tissue sections were prepared from rats pair-fed liquid diets containing 36% of total calories as either ethanol or carbohydrate (control) for 3 weeks. Immunohistochemical staining was performed using the peroxidase-antiperoxidase method after tissue sections were reacted with antibody against human P450IIE1. In control animals, immunoreactive P450IIE1 was detected only in duodenal and jejunal villous cells. After ethanol treatment, the content of P450IIE1 increased in duodenal and jejunal villi, and the enzyme was now also found in squamous epithelial cells of the cheek mucosa, tongue, esophagus, and forestomach, and in surface epithelium of the proximal colon. P450IIE1 was neither expressed nor induced by alcohol in the epithelium of stomach fundic and antral mucosa, ileum, distal colon, and rectum. When considered together with the xenobiotic activation properties of P450IIE1, these results may partly explain why alcohol abuse is a risk factor for cellular damage or cancer or both in those alimentary tract tissues in which P450IIE1 is inducible by chronic ethanol intake.
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PMID:Immunohistochemical localization of ethanol-inducible P450IIE1 in the rat alimentary tract. 220 61

The 4S polycyclic aromatic hydrocarbon (PAH)-binding protein (PBP) is a cytoplasmic protein that binds PAHs with specificity and high affinity. We have used antisera for the PBP and unlabeled peroxidase anti-peroxidase immunohistochemistry to demonstrate its possible localization in cell types known to have xenobiotic metabolizing capabilities. Cellular sites of the PBP in liver, lung and kidney of C57BL/6 and DBA/2 mice were probed. The PBP was visualized in hepatocytes throughout the liver lobule and was not preferentially located in either centrilobular or periportal areas. However, cellular heterogeneity with respect to PBP content was clearly evident in the hepatocyte population. The positive reactivity correlated with substantial levels of benzo[a]pyrene (B[a]P) binding in liver cytosol. In the lung, the PBP was found in the bronchiolar epithelium and the alveolar septa, and was localized in ciliated and non-ciliated Clara and alveolar type II cells as well as in alveolar macrophages. In the kidney, the glomeruli and epithelia of proximal and distal convoluted tubules and collecting ducts were labeled. Staining for the PBP was greatest in the apical region of the pyramid and was localized in the epithelial lining of the collecting ducts. Relatively lower levels of the PBP were detected in the lung and kidney than in the liver. Staining was localized in the cytoplasmic compartment of cells in all tissues examined. Similar immunoreactivities were exhibited in the tissues of both C57BL/6 and DBA/2 mice. Treatment with beta-naphthoflavone (beta NF) altered neither the intensity nor pattern of immunostaining. Furthermore, treatment with beta NF or isosafrole has no effect on the Kd and Bmax of B[a]P binding to liver cytosolic PBP. The results of our experiments demonstrate localization of the PBP to sites of active physiological response to PAH exposure.
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PMID:The 4S polycyclic aromatic hydrocarbon-binding protein: immunohistochemical localization in mice. 220 97

The food antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) are shown to be metabolized to covalent binding intermediates and various other metabolites by prostaglandin H synthase and horseradish peroxidase. BHA was extensively metabolized by horseradish peroxidase (80% conversion of parent BHA into metabolites) resulting in the formation of three dimeric products. Only two of these dimers were observed in prostaglandin H synthase-catalyzed reactions. In contrast to BHA, BHT proved to be a relatively poor substrate for prostaglandin synthase and horseradish peroxidase, resulting in the formation of a small amount of polar and aqueous metabolites (23% conversion of parent BHT into metabolites). With arachidonic acid as the substrate, prostaglandin H synthase catalyzed the covalent binding of [14C]BHA and [14C]BHT to microsomal protein which was significantly inhibited by indomethacin and glutathione. The covalent binding of BHA and its metabolism to dimeric products were also inhibited by BHT. In contrast, the addition of BHA enhanced the covalent binding of BHT by 400%. Moreover, in the presence of BHA, the formation of the polar and aqueous metabolites of BHT was increased and two additional metabolites, BHT-quinone methide and stilbenequinone, were detected. The increased peroxidase-dependent oxidation of BHT in the presence of BHA is proposed to occur via the direct chemical interaction of BHA phenoxyl radical with BHT or BHT phenoxyl radical. These results suggest a potential role for phenoxyl radicals in the activation of xenobiotic chemicals to toxic metabolites.
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PMID:The peroxidase-dependent activation of butylated hydroxyanisole and butylated hydroxytoluene (BHT) to reactive intermediates. Formation of BHT-quinone methide via a chemical-chemical interaction. 249 93

Neutrophil-derived oxidants have been implicated in both damage to biomolecules and the metabolic activation of xenobiotics. Since the bone marrow is a relatively neutrophil-rich tissue which is subject to xenobiotic toxicity, we have characterized the oxidant generating capability of neutrophilic cells isolated from femurs of male C57BL/6J mice. Addition of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) to neutrophil preparations (70 +/- 5% ring neutrophils and metamyelocytes) elicited superoxide anion generation, as indicated by superoxide dismutase (SOD)-inhibitable acetylated cytochrome c reduction, and oxidant-dependent chemiluminescence (CL) from luminol or lucigenin. The interaction of benzo[a]pyrene-7,8-dihydrodiol (BP-diol), a proximate carcinogenic metabolite of benzo[a]pyrene (BP), with TPA-stimulated bone marrow neutrophils resulted in azide-inhibitable CL (90%) indicative of its myeloperoxidase-dependent oxidation to an excited-state intermediate. Covalent binding of [3H]BP-diol to exogenous DNA was similarly increased 3-fold in the presence of TPA-stimulated bone marrow neutrophils. Recently, our laboratory has shown that in addition to CL, TPA-stimulated human polymorphonuclear leukocytes can activate BP-diol to an intermediate which covalently binds to DNA and elicits mutagenicity in Salmonella typhimurium TA100. These observations combined with our current results suggest a possible role for neutrophil-derived oxidants in the mechanisms of chemically-induced bone marrow toxicity.
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PMID:Neutrophil-derived oxidants as mediators of chemical activation in bone marrow. 283 35

Cytochromes P450 catalyze the insertion of one O2-derived oxygen atom into an aliphatic or aromatic molecule. P450s are best known for the metabolism of xenobiotic molecules, where hydroxylation renders insoluble hydrocarbons more soluble for easier elimination. In addition to this important catabolic function, P450s catalyze key steps in steroid and plant growth regulator metabolism. A variety of therapeutic, fungicidal, and agochemical agents that perturb these metabolic pathways very likely operate by binding in the lipophilic P450 active site and coordinating with the heme iron atom. Recent determination of a bacterial P450 crystal structure, P450cam from Pseudomonas putida, in addition to the crystal structure of four inhibited complexes, has provided some insight into the potential use of P450 as a model system for the rational design of therapeutic agents. The crystal structure has also shed light on the P450 catalytic mechanism. P450cam operates differently from peroxidase or catalase in cleaving the O-O bond, since unlike these other enzymes, P450 contains no acid-base catalytic groups near the oxygen binding site. Instead, the O2 pocket is lined with aliphatic and aromatic residues. This strongly suggests that the catalytic push required to cleave the O-O bond resides with the ability of the Cys heme ligand to donate electron density to the heme-oxy system. A comparison of the substrate-free and -bound P450cam crystal structures has revealed some interesting aspects regarding the dynamics of substrate binding.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cytochrome P450: molecular architecture, mechanism, and prospects for rational inhibitor design. 307 82

Methimazole, an irreversible, mechanism-based (suicide substrate) inhibitor of thyroid peroxidase and lactoperoxidase, also inhibits the oxidation of xenobiotics by prostaglandin hydroperoxidase. The mechanism(s) by which methimazole inhibits prostaglandin H synthase-catalyzed oxidations is not conclusively known. In studies reported here, methimazole inhibited the prostaglandin H synthase-catalyzed oxidation of benzidine, phenylbutazone, and aminopyrine in a concentration-dependent manner. Methimazole poorly supported the prostaglandin H synthase-catalyzed reduction of 5-phenyl-4-pentenyl hydroperoxide to the corresponding alcohol (5-phenyl-4-pentenyl alcohol), suggesting that methimazole is not serving as a competing reducing cosubstrate for the peroxidase. Methimazole is not a mechanism-based inhibitor of prostaglandin hydroperoxidase or horseradish peroxidase since methimazole did not inhibit the peroxidase-catalyzed, benzidine-supported reduction of 5-phenyl-4-pentenyl hydroperoxide. In contrast, methimazole inhibited the reduction of 5-phenyl-4-pentenyl hydroperoxide to 5-phenyl-4-pentenyl alcohol catalyzed by lactoperoxidase, confirming that methimazole is a mechanism-based inhibitor of that enzyme and that such inhibition can be detected by our assay. Glutathione reduces the aminopyrine cation free radical, the formation of which is catalyzed by the hydroperoxidase, back to the parent compound. Methimazole produced the same effect at concentrations equimolar to those required for glutathione. These data indicate that methimazole does not inhibit xenobiotic oxidations catalyzed by prostaglandin H synthase and horseradish peroxidase through direct interaction with the enzyme, but rather inhibits accumulation of oxidation products via reduction of a free radical-derived metabolite(s).
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PMID:The mechanism for the inhibition of prostaglandin H synthase-catalyzed xenobiotic oxidation by methimazole. Reaction with free radical oxidation products. 311 86


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