Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.11.1.7 (peroxidase)
 65,474 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In previous studies on the mutagenicity of anisidine isomers, the ortho isomer was considered to be mutagenic towards standard Ames tester strains, while the para isomer gave equivocal results. In the present study we show that both para- and ortho-anisidine isomers are mutagenic in a Salmonella typhimurium tester strain containing elevated levels of N-acetyltransferase (YG1029). p-Anisidine gave a positive mutagenic response using either hamster S9 or ram seminal vesicle microsomes (RSVM) as an activating system, while o-anisidine gave a positive response only with the hamster S9 fraction. The mutagenic response from p-anisidine was greater than with o-anisidine in each case. In tests with p-anisidine and RSVM, the addition of arachidonic acid was not necessary to observe a mutagenic response. Catalase produced a dose-dependent decrease in the mutagenic response with p-anisidine and RSVM; this indicates that endogenous hydrogen peroxide from the bacteria acts as a substrate for the peroxidase activity of RSVM prostaglandin H synthase. These results demonstrate that both anisidine isomers are mutagenic and that N-acetyltransferase enzymes play an important role in their metabolism to mutagenic species.
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PMID:Enhanced mutagenicity of anisidine isomers in bacterial strains containing elevated N-acetyltransferase activity. 137 42

We have used the Ames test in combination with prostaglandin H synthase (PHS) to study the bioactivation of benzidine as well as other aromatic amines. Previous investigations established that the formation of benzidine mutagens by PHS is dramatically enhanced in Salmonella typhimurium strains with high levels of acetyl CoA-dependent arylamine N-acetyltransferase/arylhydroxylamine O-acetyltransferase activity despite the fact that acetylation of aromatic amines decreases their susceptibility to oxidation by peroxidases. In this study, we used a new strain (YG1012) that has very high acetylation capability to investigate the metabolism and mutagenicity of benzidine and N-acetylbenzidine catalyzed by PHS (from ram seminal vesicle microsomes) and horseradish peroxidase (HRP). YG1012 bacteria rapidly acetylated benzidine to N-acetylbenzidine and N,N'-diacetylbenzidine. Preincubation of the bacteria with benzidine before addition of PHS increased the mutagenicity. Under conditions identical to those used to assess mutagenicity, PHS metabolized benzidine rapidly, but the substrate was not totally consumed, with about 40% of the original concentration remaining intact. These data suggest that conversion to N-acetylbenzidine may be the initial step in the bioactivation of benzidine in the PHS-mediated Ames assay. N-Acetylbenzidine is a cosubstrate for PHS peroxidase activity as measured by 5-phenyl-4-pentenyl hydroperoxide reduction, spectral changes, and formation of protein adducts. N-Acetylbenzidine was converted to mutagens by PHS but not HRP, with enhanced mutagenicity observed in bacteria with high acetylation activity. We used reverse- phase HPLC to characterize the metabolites of N-acetylbenzidine formed by PHS and HRP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mutagenic activation of benzidine requires prior bacterial acetylation and subsequent conversion by prostaglandin H synthase to 4-nitro-4'-(acetylamino)biphenyl. 150 68

The activities of three enzymes, tyrosinase (monophenol oxidase, MPO), N-acetyltransferase (NAT), and tyrosine aminotransferase (TAT), were studied during eumelanotic encapsulation in host larvae of Drosophila melanogaster parasitized by the wasp, Leptopilina boulardi. At 24 h postinfection there was a tenfold increase in the MPO, whereas the activities of NAT and TAT were lower than those of nonparasitized controls. The data suggest that certain developmental processes are temporarily interrupted and alterations made in the metabolism of tyrosine to provide the metabolites necessary for a successful immune response. Two strains of D. melanogaster, R and Tyr-1, were parasitized and found to be immune reactive. The Tyr-1 strain is deficient in tyrosinase during the adult stage, but this mutation was found not to affect the immune capacity of the larvae. This is the first study to document concurrent alterations in the activities of various catecholamine-metabolizing enzymes during an immune response in an insect.
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PMID:Alterations in the activities of tyrosinase, N-acetyltransferase, and tyrosine aminotransferase in immune reactive larvae of Drosophila melanogaster. 809 20

Benzidine and 4-aminobiphenyl (4-ABP) are promutagenic bicyclic aromatic amines that are activated into frameshift and base pair substitution mutagens by plant systems. Using the plant cell/microbe coincubation assay, plant-activated benzidine from 0 to 50 microM induced a concentration-response in Salmonella typhimurium. At concentrations above 5 microM, plant-activated benzidine induced frameshift and base pair substitution mutations in the N- or O-acetyltransferase over-expressing strains, DJ460, YG1024, and YG1029. With plant-activated 4-ABP, concentrations above 250 microM induced a significant mutagenic response in strains YG1024 and YG1029. A tobacco cell-free mixture, TX1MX, activated benzidine and 4-ABP into mutagenic metabolites in S. typhimurium strains YG1024, YG1029, and DJ460. The mutagenic sensitivities of plant-activated benzidine and 4-ABP were the same with two different types of plant activation systems, TX1 suspension cells and TX1MX cell-free medium. The plant activation of these aromatic amines is mediated by tobacco cell peroxidase. Plant-activated benzidine and 4-ABP are converted into intermediates that serve as substrates for bacterial or humanacetylCoA: N-hydroxyarylamine N-acetyltransferase to generate the ultimate mutagenic products.
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PMID:Plant-activation of the bicyclic aromatic amines benzidine and 4-aminobiphenyl. 902 Mar 11

4-Aminobiphenyl (ABP) is a recognized human bladder carcinogen, whose presence in cigarette smoke results in DNA adduct formation in the human urothelium. Since preliminary studies indicated that even higher levels of ABP-DNA adducts may be present in human peripheral lung, we utilized a sensitive immunochemical assay, in combination with 32P-postlabeling, to quantify the major 4-aminobiphenyl (ABP)-DNA adduct, N-(guan-8-yl)-ABP, in surgical samples of peripheral lung tissue from smokers and ex-smokers. No differences in adduct levels were detected between smokers and ex-smokers by immunoassay. In contrast, the 32P-postlabeling method showed statistically significant differences between adduct levels in smokers and ex-smokers; however, a relatively high background of smoking-related adducts chromatograph near the major ABP adducts and may compromise estimation of the level of ABP-DNA adducts in smokers. Furthermore, the levels measured by 32P-postlabeling were 20- to 60-fold lower than that measured by immunoassay. Since 32P-postlabeling may underestimate and immunochemical assays may overestimate adduct levels in the lung, selected samples were also evaluated by GC/MS. The immunochemical and GC/MS data were concordant, leading us to conclude that N-(guan-8-yl)-ABP adducts were not related to smoking status. Since ABP-DNA adduct levels in human lung did not correlate with smoking status as measured by immunoassay and GC/MS, the metabolic activation capacity of human lung microsomes and cytosols was examined to determine if another exposure (e.g., 4-nitrobiphenyl) might be responsible for the adduct. The rates of microsomal ABP N-oxidation were below the limit of detection, which was consistent with a lack of detectable cytochrome P4501A2 in human lung. N-Hydroxy-ABP O-acetyltransferase (but not sulfotransferase) activity was detected in cytosols and comparative measurements of N-acetyltransferase (NAT) using p-aminobenzoic acid and sulfamethazine indicated that NAT1 and NAT2 contributed to this activity. 4-Nitrobiphenyl reductase activity was found in lung microsomes and cytosols, with the reaction yielding ABP and N-hydroxy-ABP. Lung microsomes also demonstrated high peroxidative activation of ABP, benzidine, 4,4'-methylene-bis(2-chloroaniline), 2-aminofluorene, and 2-naphthylamine. The preferred co-oxidant was hydrogen peroxide and the reaction was strongly inhibited by sodium azide but not by indomethacin or eicosatetraynoic acid, which suggested the primary involvement of myeloperoxidase rather than prostaglandin H synthase or lipoxygenase. This was confirmed by immunoinhibition and immunoprecipitation studies using solubilized human lung microsomes and antisera specific for myeloperoxidase. These data suggest that ABP-DNA adducts in human lung result from some environmental exposure to 4-nitrobiphenyl. The bioactivation pathways appear to involve: (1) metabolic reduction to N-hydroxy-ABP and subsequent O-acetylation by NAT1 and/or NAT2; and (2) metabolic reduction to ABP and subsequent peroxidation by myeloperoxidase. The myeloperoxidase activity appears to be the highest peroxidase activity measured in mammalian tissue and is consistent with the presence of neutrophils and polymorphonuclear leukocytes surrounding particulate matter derived from cigarette smoking.
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PMID:Immunochemical, 32P-postlabeling, and GC/MS detection of 4-aminobiphenyl-DNA adducts in human peripheral lung in relation to metabolic activation pathways involving pulmonary N-oxidation, conjugation, and peroxidation. 928 89

We have analyzed the tumor biopsies of 45 patients with bladder cancer for p53 mutations by direct sequencing. In addition to N-acetyltransferase-2 (NAT2) and GSTM1 allelisms, which were examined previously, we have analyzed the genetic polymorphisms of GSTT1, GSTP1, COMT, NQO1, TS-SULT and MPO in buffy coat DNA using PCR-based methods. All subjects were interviewed through a questionnaire on smoking, dietary habits and other risk factors. No specific pattern was evident for p53 mutations. Eight out of ten mutations occurred in grade 3 tumors. All p53 mutations occurred in subjects with the COMT mutated allele (p=0.03). The prevalence of cases with p53 mutations was 3.5-fold higher in subjects with wild type than in those with variant GSTP1 alleles (p=0.03). The other polymorphisms investigated were not associated with p53 mutations.
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PMID:Impact of polymorphisms in xeno(endo)biotic metabolism on pattern and frequency of p53 mutations in bladder cancer. 1076 40

Treatment-related leukemias are one of the most devastating late complications of cancer therapy. Patients with rare cancer predisposition syndromes including neurofibromatosis type 1 and inherited p53 mutations are at an increased risk for this complication. Other patients may have increased susceptibility because they possess common genetic polymorphisms in drug-metabolizing enzymes that result in impaired detoxification of chemotherapy or inefficient repair of drug-induced genetic damage. We review studies that have identified a potential role for polymorphisms in the genes encoding the glutathione-S-transferases (GSTs), NAD(P) H: quinone oxidoreductase, myeloperoxidase, N-acetyltransferase (NATs), cytochrome P450 (CYP) 1A1 and 3A4, methylenetetrahydrofolate reductase (MTHFR), cystathionine-beta-synthase (CBS), and others in the etiology of primary or secondary acute leukemias, and therapy-related complications. The identification of high risk polymorphisms and use of pharmacogenetically-guided therapies holds promise to improve the outcome of cancer therapy and reduce the risk of treatment-related leukemias.
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PMID:Genetic predisposition and treatment-related leukemia. 1134 Jun 9

The origin of acute lymphoblastic leukemia (ALL), the most common pediatric cancer, can be explained by a combination of genetic factors and environmental exposure. The environmental toxicants to which an individual is exposed are biotransformed and eliminated from the body after metabolic conversion mediated by Phase I and Phase II xenobiotic-metabolizing enzymes. Phase I enzymes catalyze hydroxylation, reduction and oxidation reactions of xenobiotics (carcinogens/drugs), often converting them into more active or toxic compounds. Phase II enzymes catalyze conjugation reactions (glucuronidation, acetylation, methylation), thereby converting the metabolites into non-reactive, water-soluble products that are eliminated from the organism. The genetic polymorphism underlying the variation in enzyme activity can modify susceptibility to diverse adult cancers, probably by influencing the activation and removal of toxicants or drugs. Here we present an overview of the role of genetic variants of certain Phase I and Phase II enzymes in the development of childhood ALL, a good model for such studies because of its short latency period. The genetic contribution to the development of ALL is examined by association studies that analyze the loci of Phase I enzymes (cytochrome P-450, myeloperoxidase) and Phase II enzymes (quinone-oxidoreductase, glutathione-S-transferase, N-acetyltransferase). The loci of the enzyme variants CYPlA1, CYP2E1, NQO1, GSTM1, GSTP1, NAT2 are associated with disease development, and evidence of gene-gene interactions has emerged as well. Despite the improvements in treatment, resistant cases of ALL remain a leading cause of cancer-related death in children. Although the underlying mechanism of drug resistance is not well understood, differences in the capacity of ALL patients to process drugs and environmental carcinogens could play a role by modifying the risk of recurrent malignancy, as well as the response to therapy. Therefore, polymorphic genes encoding carcinogen- and drug-metabolizing enzymes may not only increase the risk of ALL but also influence the risk of relapse in patients. We found that the prognosis of patients with CYPlA1 and NQO1 variants was worse than that of patients who lack these variants. We conclude that genotyping ALL patients for functional polymorphisms of candidate genes can become an important tool in predicting disease outcome.
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PMID:Childhood acute lymphoblastic leukemia: genetic determinants of susceptibility and disease outcome. 1204 82

The many physiological, biochemical, and structure differences between rodents and humans, especially with regard to gestation and fetal development, invite questions as to the utility of rodent models for the prediction of risk of perinatal carcinogenesis in humans and for extrapolation of mechanistic studies. Here, the relevance of basic generalities, derived from rodent perinatal studies, to human contexts is considered. The cross-species usefulness of these generalities was upheld by the example of carcinogen activation and detoxification as determining factors. These have been established in rodent studies and recently indicted in humans by investigations of genetic polymorphisms in cytochromes P450, N-acetyltransferase, myeloperoxidase, quinone reductase, and glutathione S-transferase. Also, published data have been analyzed comparatively for diethylstilbestrol and irradiation, the two known human transplacental carcinogenic agents. At similar doses to those experienced by humans, both diethylstilbestrol and X- and gamma-irradiation in rodents and dogs yielded increased tumors at rates similar to those for humans. In rodents, there was a clearly negative relationship between total diethylstilbestrol dose and tumors per dose unit, and a similar pattern was suggested for radiation. Diethylstilbestrol had transgenerational effects that did not diminish over three generations. Overall, this analysis of the published literature indicates that there are basic qualitative and quantitative similarities in the responsiveness of human and rodent fetuses to carcinogens, and that dose effects may be complex and in need of further investigation.
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PMID:Predictive values of traditional animal bioassay studies for human perinatal carcinogenesis risk determination. 1531 88

Isoniazid is a frontline drug used in the treatment of tuberculosis (TB). Isoniazid is a prodrug, requiring activation in the mycobacterial cell by the catalase/peroxidase activity of the katG gene product. TB kills two million people every year and the situation is getting worse due to the increase in prevalence of HIV/AIDS and emergence of multidrug-resistant strains of TB. Arylamine N-acetyltransferase (NAT) is a drug-metabolizing enzyme (E.C. 2.1.3.5). NAT can acetylate isoniazid, transferring an acetyl group from acetyl coenzyme A onto the terminal nitrogen of the drug, which in its N-acetylated form is therapeutically inactive. The bacterium responsible for TB, Mycobacterium tuberculosis, contains and expresses the gene encoding the NAT protein. Isoniazid binds to the NAT protein from Salmonella typhimurium and we report here the mode of binding of isoniazid in the NAT enzyme from Mycobacterium smegmatis, closely related to the M. tuberculosis and S. typhimurium NAT enzymes. The mode of binding of isoniazid to M. smegmatis NAT has been determined using data collected from two distinct crystal forms. We can say with confidence that the observed mode of binding of isoniazid is not an artifact of the crystallization conditions used. The NAT enzyme is active in mycobacterial cells and we propose that isoniazid binds to the NAT enzyme in these cells. NAT activity in M. tuberculosis is likely therefore to modulate the degree of activation of isoniazid by other enzymes within the mycobacterial cell. The structure of NAT with isoniazid bound will facilitate rational drug design for anti-tubercular therapy.
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PMID:Binding of the anti-tubercular drug isoniazid to the arylamine N-acetyltransferase protein from Mycobacterium smegmatis. 1572 51


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