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)

Cytochrome P450 in the mitochondria of the adrenal cortex functions in the monooxygenation reactions for the biosynthesis of various steroid hormones, such as cholesterol side chain cleavage, hydroxylation at 11 beta-position and that at 18-position of the steroid structure. The cytochrome is firmly associated with the mitochondrial membrane and therefore can be isolated only by the aid of ionic or non-ionic detergent. Recently, two cytochromes P450 each catalyzing a specified reaction have been purified to a homogeneous state, that is, P450scc having cholesterol side chain cleavage activity and P45011 beta having 11 beta-hydroxylation activity. The properties of these purified P450's as well as the other components of the monooxygenase system, adrenodoxin and adrenodoxin reductase, are, therefore, summarized and compared to those of P450 in the mitochondrial preparation in situ. Among many findings, both purified cytochromes P450 were revealed to be a low-spin type hemoprotein and their spin states were changed to a high-spin state by being complexed with the corresponding substrate. The binding of a substrate also facilitated the reduction of the cytochrome and appeared to increase the stability of the oxygenated form of cytochrome P450. These effects are important from the point of view that the primary role of the heme of cytochrome P450 is the activation of molecular oxygen. In addition, the results of our detailed kinetic studies on the transfer of electrons from adrenodoxin to cytochrome P450 in the reconstituted system have also been described. Finally, the topology of adrenodoxin and the reductase were shown to be on the inner mitochondrial membrane by a peroxidase-labeled antibody method.
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PMID:Cytochrome P450 in adrenocortical mitochondria. 22 25

Thianthrene 5-oxide (T-5-O), which is oxidized to the 5,10- and 5,5-dioxides, respectively, by electrophilic and nucleophilic agents, has been used to determine the electronic properties of hemoprotein oxidizing species. Cytochrome P450 oxidizes T-5-O to the 5,10- rather than the 5,5-dioxide but oxidizes the 5,5-dioxide rapidly and the 5,10-dioxide slowly to the 5,5,10-trioxide. Chloroperoxidase oxidizes T-5-O to the 5,10-dioxide but very poorly oxidizes it further to the 5,5,10-trioxide. It does, however, readily oxidize the 5,5-dioxide to the trioxide. The oxidizing species of cytochrome P450 and chloroperoxidase are thus comparably electrophilic, but the former is more powerful. T-5-O is not detectably oxidized by horseradish peroxidase/H2O2 but is oxidized exclusively to the 5,5-dioxide when the peroxide is replaced by dihydroxyfumaric acid (DHFA). The oxygen incorporated into the 5,5-dioxide in this reaction derives from molecular oxygen. This is consistent with the involvement of a DHFA-derived co-oxidizing species. Oxidation of T-5-O by human hemoglobin and H2O2 yields the 5,5- and 5,10-dioxides and the 5,5,10-trioxide. The oxygen in these products derives primarily (greater than 80%) from H2O2. Hemoglobin and H2O2 thus form both a P450-like electrophilic oxidant (5,10-dioxide) and a peroxide-derived nucleophilic oxidant (5,5-dioxide). A large difference in the cis:trans ratios of the 5,10-dioxides produced from T-5-O by cytochrome P450 (1.3:1) and chloroperoxidase (2.5:1) vs hemoglobin (0.1:1) suggests that the hemoglobin active site severely constrains the geometry of the electrophilic oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Thianthrene 5-oxide as a probe of the electrophilicity of hemoprotein oxidizing species. 152 69

The cytochrome P450 enzyme systems catalyze the metabolism of a wide variety of naturally occurring and foreign compounds by reactions requiring NADPH and O2. Cytochrome P450 also catalyzes peroxide-dependent hydroxylation of substrates in the absence of NADPH and O2. Peroxidases such as chloroperoxidase and horseradish peroxidase catalyze peroxide-dependent reactions similar to those catalyzed by cytochrome P450. The kinetic and chemical mechanisms of the NADPH and O2-supported dealkylation reactions catalyzed by P450 have been investigated and compared with those catalyzed by P450 and peroxidases when the reactions are supported by peroxides. Detailed kinetic studies demonstrated that chloroperoxidase- and horseradish peroxidase-catalyzed N-demethylations proceed by a Ping Pong Bi Bi mechanism whereas P450-catalyzed O-dealkylations proceed by sequential mechanisms. Intramolecular isotope effect studies demonstrated that N-demethylations catalyzed by P450s and peroxidases proceed by different mechanisms. Most hemeproteins investigated catalyzed these reactions via abstraction of an alpha-carbon hydrogen whereas reactions catalyzed by P-450 and chloroperoxidase proceeded via an initial one-electron oxidation followed by alpha-carbon deprotonation. 18O-Labeling studies of the metabolism of NMC also demonstrated differences between the peroxidases and P450s. Because the hemeprotein prosthetic groups of P450, chloroperoxidase, and horseradish peroxidase are identical, the differences in the catalytic mechanisms result from differences in the environments provided by the proteins for the heme active site. It is suggested that the axial heme-iron thiolate moiety in P450 and chloroperoxidase may play a critical role in determining the mechanism of N-demethylation reactions catalyzed by these proteins.
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PMID:Mechanisms of cytochrome P450 and peroxidase-catalyzed xenobiotic metabolism. 153 57

The nature of the enzyme(s) catalyzing the major metabolic pathway (5'-hydroxylation) of oxicam NSAIDs was investigated in subcellular preparations of human liver tissue. Microsomal, but not cytosolic, fractions catalyzed the 5'-hydroxylation of tenoxicam. This reaction required NADPH and was inhibited by various nonselective P450 inhibitors (CO, SKF-525A, ketoconazole), but not by the peroxidase inhibitor NaN3. Tenoxicam 5'-hydroxylation exhibited simple Michaelis-menten kinetics compatible with catalysis by a single enzyme, but it strongly inhibited its own oxidation at concentrations higher than 100-150 microM. Piroxicam competitively inhibited tenoxicam 5'-hydroxylation and, conversely, tenoxicam competitively inhibited piroxicam 5'-hydroxylation. Tenoxicam 5'-hydroxylation kinetics were similar in microsomes from one poor and five extensive metabolizers of debrisoquin (CYP2D6). Dextromethorphan (CYP2D6 prototype substrate) and midazolam (CYP3A prototype substrate) had no influence on tenoxicam 5'-hydroxylation, whereas mephenytoin, tolbutamide and sulfaphenazole (Ki = 0.1 microM) inhibited it. This indicates that the 5'-hydroxylation of both piroxicam and tenoxicam is predominantly catalyzed by at least one cytochrome P450 isozyme of the CYP2C subfamily.
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PMID:In vitro oxidation of oxicam NSAIDS by a human liver cytochrome P450. 164 Aug 8

Previous anatomical and histochemical studies suggested that interstitial cells were the only steroidogenic cells in the theca layer of small follicles of the chicken ovary. However, the precise cellular site of steroid production in the small follicles is not certain. Therefore, our goal was to identify steroidogenic cells in small follicles (less than 10 mm in diameter) of the chicken ovary which have not entered the follicular hierarchy by localizing steroidogenic enzymes with immunocytochemistry. Polyclonal antisera used were anti-cholesterol side-chain-cleavage cytochrome P450 (P450scc), anti-17 alpha-hydroxylase cytochrome P450 (P450c17), and anti-aromatase cytochrome P450 (P450arom) for pregnenolone-, androgen-, and estrogen-producing cells, respectively. Ovaries were collected 2 hr after oviposition and embedded in Paraplast after fixation with 4% paraformaldehyde, 10% formaldehyde, or Bouin's solution. Tissues were sectioned (4-6 microns) and sections were mounted on poly-L-lysine coated slides. Sections were incubated overnight at room temperature with each specific antiserum raised in rabbits against cytochrome P450 steroidogenic enzymes or normal rabbit serum as a control and were immunostained with an avidin-biotin-peroxidase complex. Immunoreactivity for the P450 enzymes was absent in the granulosa layer but was present in the theca layer of the small follicles (less than 10 mm in diameter). Interstitial cells in the single theca layer of cortical follicles embedded in the ovarian cortex (less than 1 mm in diameter) contained P450scc and P450c17. Cells which contained P450arom, identified as aromatase cells, surrounded the interstitial cells in the theca layer.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Immunolocalization of steroidogenic cells in small follicles of the chicken ovary: anatomical arrangement and location of steroidogenic cells change during follicular development. 178 5

Few nonphagocytic cells are known to generate reactive oxygen intermediates. Based on horseradish peroxidase-dependent, catalase-inhibitable oxidation of fluorescent scopoletin, seven human tumor cell lines constitutively elaborated H2O2 at rates (up to 0.5 nmol/10(4) cells/h) large enough that cumulative amounts at 4 h were comparable to the amount of H2O2 produced by phorbol ester-triggered neutrophils. Superoxide dismutase-inhibitable ferricytochrome c reduction was detectable at much lower rates. H2O2 production was inhibited by diphenyleneiodonium, a flavoprotein binder (concentration producing 50% inhibition, 0.3 microM), and diethyldithiocarbamate, a divalent cation chelator (concentration producing 50% inhibition, 3 microM), but not by cyanide or azide, inhibitors of electron transport, or by agents that inhibit xanthine oxidase, polyamine oxidase, or cytochrome P450. Cytochrome b559, present in human phagocytes and lymphocytes, was undetectable in these tumor cells by a sensitive spectrophotometric method. Mouse fibroblasts transfected with human tyrosinase complementary DNA made melanin, but not H2O2. Constitutive generation of large amounts of reactive oxygen intermediates, if it occurs in vivo, might contribute to the ability of some tumors to mutate, inhibit antiproteases, injure local tissues, and therefore promote tumor heterogeneity, invasion, and metastasis.
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PMID:Production of large amounts of hydrogen peroxide by human tumor cells. 184 17

The distribution of phenytoin-inducible cytochrome P450 in non-treated mouse brain and spinal cord was analysed immunohistochemically using polyclonal antibodies against phenytoin-induced mouse cerebral microsomal P450. This P450 protein was proved in Ouchterlony [Volk B. et al. (1988) Neurosci. Lett. 84, 219-224], Western blot, and immunohistochemical analyses to be reactive to the specific antibodies and an IgG fraction raised against phenobarbital-induced rat liver microsomal P450IIB1. The phenytoin-induced P450 is designated P450IIB1* because immunologically it is comparable with P450IIB1; however, it has not yet been analysed for other characteristics of this enzyme. Immunocytochemistry was performed on acetone-fixed serial cryosections of the whole brain using the avidin-biotin-peroxidase detection system. Negative controls included incubations with preimmune serum of the immunized animal instead of the primary antibody and preabsorption of the antibody with the corresponding immunogen. The pattern of immunoreactive sites indicates that P450IIB1* is not distributed evenly throughout the CNS. It was found to be restricted to only some cellular populations. The most striking aspect of immunostaining was a predominant reactivity in the evolutionary old brain parts. Neuropil and neuronal staining was found in the spinal cord (motor neurons of the ventral horn), medulla oblongata (hypoglossal nuclei, magnocellular part of the lateral reticular nuclei), pons (trigeminal, facial, cochlear and pontine nuclei), cerebellum (granule cells), midbrain (dorsal raphe nucleus) and limbic lobe (hippocampal pyramidal cells). Neuropil reactivity alone appeared in cerebellar nuclei, midbrain, thalamus, basal ganglia, neopallium and olfactory brain. Generally, pia mater/arachnoid, ependyma, choroid plexus, vascular system and some astrocytic populations were found to be strongly P450IIB1* immunoreactive. In comparison with astroglia, which is characterized by glial fibrillary acidic protein-positiveness, the astrocytes, which are also P450IIB1* reactive, occurred only in subpial and subependymal layers, and in large fiber tracts of the spinal cord and brainstem, where they were attached to the vascular system. Otherwise, the glial fibrillary acidic protein-positive astrocytes were not P450IIB1* immunoreactive in the cerebellar molecular layer (fibers of Bergmann glia), in remaining neuropils and in white matter areas.
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PMID:Mapping of phenytoin-inducible cytochrome P450 immunoreactivity in the mouse central nervous system. 186 74

NADPH-dependent oxidation of 1,3-butadiene by mouse liver microsomes or H2O2-dependent oxidation by chloroperoxidase produced both butadiene monoxide and crotonaldehyde; methyl vinyl ketone and 2,3- and 2,5- dihydrofuran were not detected. The crotonaldehyde to butadiene monoxide ratio remained constant over time in both the microsomal and the chloroperoxidase reactions; however, much more crotonaldehyde was produced by chloroperoxidase than microsomes; crotonaldehyde was not detected when reference samples of butadiene monoxide were used in control incubations containing NADPH and microsomes or H2O2 and chloroperoxidase. Moreover, incubations of 1,3-butadiene with horseradish peroxidase and H2O2, or microsomes and H2O2 or arachidonic acid did not result in the oxidation of 1,3-butadiene. In microsomes, metabolite formation was dependent on incubation time, NADPH, and protein concentrations and did not change when the 1,3-butadiene pressure was varied between 24 and 52 cm Hg. Inclusion of the cytochrome P450 inhibitor 1-benzylimidazole inhibited 1,3-butadiene metabolism, but inclusion of KCN, catalase, or superoxide dismutase had no effect. These results support the role of cytochrome P450 in 1,3-butadiene oxidation by mouse liver microsomes. The formation of crotonaldehyde but not methyl vinyl ketone by cytochrome P450 or chloroperoxidase indicates regioselectivity in the oxygen transfer from the hemoproteins to 1,3-butadiene. The intermediates formed may undergo either ring closure to form butadiene monoxide or a hydrogen shift to form 3-butenal which tautomerizes to produce crotonaldehyde. Evidence for this tautomerization was obtained by the finding that 3-buten-1-ol, an alternative precursor of 3-butenal, was oxidized to crotonaldehyde under incubation conditions similar to that used for 1,3-butadiene.
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PMID:Mechanisms of 1,3-butadiene oxidations to butadiene monoxide and crotonaldehyde by mouse liver microsomes and chloroperoxidase. 189 52

Rat liver microsomes contain a membrane-bound GSH S-transferase (GSH-tr), an enzyme that is involved in the detoxication of xenobiotics. Also located on rat liver microsomes is the cytochrome P450 system, an enzyme complex that catalyzes the conversion of several xenobiotics into reactive intermediates. In this study, it was demonstrated that reactive products from alpha-methyldopa formed by the cytochrome P450 system are able to stimulate microsomal GSH-tr. Also, products formed from alpha-methyldopa that are generated by H2O2-horseradish peroxidase and tyrosinase are able to stimulate the activity of microsomal GSH-tr. GSH was able to prevent the activation of microsomal GSH-tr. Our results indicate that the ortho-quinone or semi-ortho-quinone radical of alpha-methyldopa is responsible for the stimulation of microsomal GSH-tr, probably via arylation of the free sulfhydryl group of microsomal GSH-tr. This conclusion was supported by the observation that 4-methyl-ortho-quinone itself was able to stimulate microsomal GSH-tr via sulfhydryl arylation. Our results are in conformity with the hypothesis that reactive products formed by the cytochrome P450 complex are able to stimulate microsomal GSH-tr and possibly in this way enhance their detoxication.
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PMID:Activation of the microsomal glutathione S-transferase by metabolites of alpha-methyldopa. 189 94

Differences in expression of cytochrome P450 forms and their functions in different organs and cell types could determine the response of those cells and organs to xenobiotics. Recently, we described the cellular localization of cytochrome P450IA1 (P450E) induced in 10 organs or organ systems of the fish, Stenotomus chrysops (scup) treated with 3,3',4,4'-tetrachlorobiphenyl or with 2,3,7,8-tetrachlorodibenzofuran. (R.M. Smolowitz, M.E. Hahn, and J.J. Stegeman, Drug Metab. Dispos. 19, 113, 1991). Here we describe the presence and localization of P450IA1 in organs of scup sampled directly from an environment contaminated by chlorinated biphenyls and bibenzofurans, the outer New Bedford Harbor of Massachusetts. Western blot analysis of microsomes from selected organs (liver, kidney, gill, and heart), using monoclonal antibody 1-12-3, revealed induced levels of P450IA1 in each. The localization of P450IA1 in these and other organs was determined in sections prepared by standard histological methods and stained with MAb 1-12-3 in an indirect peroxidase labeling method. P450IA1 was detected in multiple cell types in liver, including hepatic, pancreatic, and vascular tissue. Kidney and gut also showed prominent P450IA1 levels in epithelial structures and in vascular endothelial cells. Specific staining was detected in endothelial cells, but not other cell types, in heart, gill, spleen, testis, ovary, nose, and brain. In heart, the staining was present in the endocardium of atrium and ventricle, and endothelium of the coronary vasculature and great vessels. The results demonstrate that P450IA proteins are induced in many organs of fish exposed to environmental chemicals in the wild, with patterns of cellular localization like those seen in fish experimentally treated with known inducers. The strong staining of P450IA1 in endothelial cells in all organs examined supports experimental results indicating that endothelium is a major site of P450IA1 induction. Our results indicate further that immunohistochemistry is a useful method for detecting P450 induction as a biomarker for exposure.
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PMID:Immunohistochemical localization of environmentally induced cytochrome P450IA1 in multiple organs of the marine teleost Stenotomus chrysops (Scup). 194 16


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