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Robert J Turesky - One of the best experts on this subject based on the ideXlab platform.

  • metabolism of 2 amino 3 8 dimethylimidazo 4 5 f quinoxaline in human hepatocytes 2 amino 3 methylimidazo 4 5 f quinoxaline 8 carboxylic acid is a major Detoxication pathway catalyzed by cytochrome p450 1a2
    Chemical Research in Toxicology, 2001
    Co-Authors: Sophie Langouet, F P Guengerich, Dieter H Welti, Nathalie Kerriguy, Laurent B Fay, T Huynhba, Jovanka Markovic, Andre Guillouzo, Robert J Turesky
    Abstract:

    Metabolic pathways of the mutagen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) remain incompletely characterized in humans. In this study, the metabolism of MeIQx was investigated in primary human hepatocytes. Six metabolites were characterized by UV and mass spectroscopy. Novel metabolites were additionally characterized by 1H NMR spectroscopy. The carcinogenic metabolite, 2-(hydroxyamino)-3,8-dimethylimidazo[4,5-f]quinoxaline, which is formed by cytochrome P450 1A2 (P450 1A2), was found to be transformed into the N(2)-glucuronide conjugate, N(2)-(beta-1-glucosiduronyl)-2-(hydroxyamino)-3,8-dimethylimidazo[4,5-f]quinoxaline. The phase II conjugates N(2)-(3,8-dimethylimidazo[4,5-f]quinoxalin-2-yl)sulfamic acid and N(2)-(beta-1-glucosiduronyl)-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, as well as the 7-oxo derivatives of MeIQx and N-desmethyl-MeIQx, 2-amino-3,8-dimethyl-6-hydro-7H-imidazo[4,5-f]quinoxalin-7-one (7-oxo-MeIQx), and 2-amino-6-hydro-8-methyl-7H-imidazo[4,5-f]quinoxalin-7-one (N-desmethyl-7-oxo-MeIQx), thought to be formed exclusively by the intestinal flora, were also identified. A novel metabolite was characterized as 2-amino-3-methylimidazo[4,5-f]quinoxaline-8-carboxylic acid (IQx-8-COOH), and it was the predominant metabolite formed in hepatocytes exposed to MeIQx at levels approaching human exposure. IQx-8-COOH formation is catalyzed by P450 1A2. This metabolite is a Detoxication product and does not induce umuC gene expression in Salmonella typhimurium strain NM2009. IQx-8-COOH is also the principal oxidation product of MeIQx excreted in human urine [Turesky, R., et al. (1998) Chem. Res. Toxicol. 11, 217-225]. Thus, P450 1A2 is involved in both the metabolic activation and Detoxication of this procarcinogen in humans. Analogous metabolism experiments were conducted with hepatocytes of untreated rats and rats pretreated with the P450 inducer 3-methylcholanthrene. Unlike human hepatocytes, the rat cell preparations did not produce IQx-8-COOH but catalyzed the formation of 2-amino-3,8-dimethyl-5-hydroxyimidazo[4,5-f]quinoxaline as a major P450-mediated Detoxication product. In conclusion, our results provide evidence of a novel MeIQx metabolism pathway in humans through P450 1A2-mediated C(8)-oxidation of MeIQx to form IQx-8-COOH. This biotransformation pathway has not been detected in experimental animal species. Considerable interspecies differences exist in the metabolism of MeIQx by P450s, which may affect the biological activity of this mutagen and must be considered when assessing human health risk.

Thomas W. Kensler - One of the best experts on this subject based on the ideXlab platform.

  • generation of a new model rat nrf2 knockout rats are sensitive to aflatoxin b1 toxicity
    Toxicological Sciences, 2016
    Co-Authors: Keiko Taguchi, Thomas W. Kensler, Patricia A. Egner, Misaki Takaku, Masanobu Morita, Takehito Kaneko, Tomoji Mashimo, Masayuki Yamamoto
    Abstract:

    Abstract THE TRANSCRIPTION FACTOR NRF2: (NF-E2-related-factor 2) REGULATES A BATTERY OF ANTIOXIDATIVE STRESS-RESPONSE GENES AND Detoxication GENES, AND NRF2 KNOCKOUT LINES OF MICE HAVE BEEN CONTRIBUTING CRITICALLY TO THE CLARIFICATION OF ROLES THAT NRF2 PLAYS FOR CELL PROTECTION HOWEVER, THERE ARE APPARENT LIMITATIONS IN USE OF THE MOUSE MODELS FOR INSTANCE, RATS EXHIBIT MORE SUITABLE FEATURES FOR TOXICOLOGICAL OR PHYSIOLOGICAL EXAMINATIONS THAN MICE IN THIS STUDY, WE GENERATED 2 LINES OF NRF2 KNOCKOUT RATS BY USING A GENOME EDITING TECHNOLOGY; 1 LINE HARBORS A 7-BP DELETION Δ7 AND THE OTHER LINE HARBORS A 1-BP INSERTION +1 IN THE NRF2 GENE IN THE LIVERS OF RATS HOMOZYGOUSLY DELETING THE NRF2 GENE, AN ACTIVATOR OF NRF2 SIGNALING, CDDO-IM, COULD NOT INDUCE EXPRESSION OF REPRESENTATIVE NRF2 TARGET GENES TO EXAMINE ALTERED TOXICOLOGICAL RESPONSE, WE TREATED THE NRF2 KNOCKOUT RATS WITH AFLATOXIN B1 AFB1, A CARCINOGENIC MYCOTOXIN THAT ELICITS GENE MUTATIONS THROUGH BINDING OF ITS METABOLITES TO DNA AND FOR WHICH THE RAT HAS BEEN PROPOSED AS A REASONABLE SURROGATE FOR HUMAN TOXICITY INDEED, IN THE NRF2 KNOCKOUT RAT LIVERS THE ENZYMES OF THE AFB1 Detoxication PATHWAY WERE SIGNIFICANTLY DOWNREGULATED SINGLE DOSE ADMINISTRATION OF AFB1 INCREASED HEPATOTOXICITY AND BINDING OF AFB1-N7-GUANINE TO HEPATIC DNA IN NRF2 KNOCKOUT RATS COMPARED WITH WILD-TYPE NRF2 KNOCKOUT RATS REPEATEDLY TREATED WITH AFB1 WERE PRONE TO LETHALITY AND CDDO-IM WAS NO LONGER PROTECTIVE THESE RESULTS DEMONSTRATE THAT NRF2 KNOCKOUT RATS ARE QUITE SENSITIVE TO AFB1 TOXICITIES AND THIS RAT GENOTYPE EMERGES AS A NEW MODEL ANIMAL IN TOXICOLOGY.

  • Chemoprevention by Inducers of Carcinogen Detoxication Enzymes
    2013
    Co-Authors: Thomas W. Kensler
    Abstract:

    One of the major mechanisms of chemical protection against carcinogenesis, mutagenesis, and other forms of toxicity mediated by electrophiles is the induction of enzymes involved in their metabolism, particularly phase 2 enzymes such as glutathione S-transferases (GSTs), uridine diphosphate-glucuronosyltransferases, and NAD(P)H:quinone reductase. Furthermore, induction of phase 2 enzymes appears to be a sufficient condition for obtaining chemoprevention and can be achieved in many target tissues by administering any of a diverse array of naturally occurring and synthetic chemical agents. One class of chemopreventive agents, 1,2-dithiole-3-thiones, was developed on the basis of their potent activity in rodent tissues as inducers of GSTs. A substituted dithiolethione, oltipraz 14-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thionel, is an effective inhibitor of aflatoxin Bl-mediated hepatocarcinogenesis in the rat. Oltipraz produces dramatic decreases in the levels of aflatoxin-DNA adducts in the liver as well as in the urinary levels of the depurination product aflatoxin-N7-guanine. Corresponding increases are seen in the biliary elimination of aflatoxin-glutathione conjugates. Administration of oltipraz results in 3- to 4-fold increases in hepatic cytosolic GST activities and mRNA levels for some x, p and X isoforms. Nuclear run-on assays have indicated that oltipraz treatment elevates rates of transcription o

  • nrf2 control of sensitivity to carcinogens
    Archives of Toxicology, 2011
    Co-Authors: Stephen L Slocum, Thomas W. Kensler
    Abstract:

    Induction of enzymes that enhance the Detoxication of chemical carcinogens has been a broadly effective strategy for chemoprevention of experimental carcinogenesis in rodent models. Several inducing agents are now in clinical trials to evaluate utility for prevention of cancers associated with unavoidable high exposures to environmental carcinogens. The successes of these pre-clinical and clinical interventions lead to studies to define the molecular basis for protection by these agents, which now include phenolic antioxidants, dithiolethiones, isothiocyanates, and triterpenoids. In the mid-1990s, the NF-E2-related factor 2 (Nrf2) transcription factor was identified as a key regulator of the inducible expression of enzymes such as glutathione S-transferases and NAD(P)H: quinone oxidoreductase in catalyzing the Detoxication of reactive electrophiles and oxidants that contribute to the formation of mutations and ultimately cancers. Nrf2 is now recognized to regulate a broad cytoprotective, transcriptional response leading to prevention of damage to DNA, proteins and lipids; recognition, repair and removal of macromolecular damage; and tissue renewal following toxic assaults. Highlighting the importance of this pathway as a determinant of susceptibility to carcinogenesis, multiple studies now demonstrate enhanced incidence, multiplicity, and/or tumor burden in Nrf2-disrupted mice compared to wild-type in models of inflammation and colon cancer, bladder cancer, lung disease and cancer, stomach cancer, mammary cancer, skin cancer, and hepatocarcinogenesis.

  • modulation of gene expression by cancer chemopreventive dithiolethiones through the keap1 nrf2 pathway identification of novel gene clusters for cell survival
    Journal of Biological Chemistry, 2003
    Co-Authors: Mi Kyoung Kwak, Ken Itoh, Nobunao Wakabayashi, Masayuki Yamamoto, Hozumi Motohashi, Thomas W. Kensler
    Abstract:

    Abstract Enzyme inducers such as 3H-1,2-dithiole-3-thione (D3T) enhance the Detoxication of environmental carcinogens and protect against neoplasia. The putative molecular sensor for inducers is Keap1, a sulfhydryl-rich protein that sequesters the transcription factor Nrf2 in the cytoplasm. Expression of these Detoxication enzymes is blunted in nrf2-deficient mice; moreover, these mice are more sensitive to carcinogenesis, and the protective actions of dithiolethiones are lost with nrf2 disruption. Hepatic gene expression profiles were examined by oligonucleotide microarray analysis in vehicle- or D3T-treated wild-type mice as well as in nrf2 single and keap1-nrf2double knockout mice to identify those genes regulated by the Keap1-Nrf2 pathway. Transcript levels of 292 genes were elevated in wild-type mice 24 h after treatment with D3T; 79% of these genes were induced in wild-type, but notnrf2-deficient mice. Thesenrf2-dependent, D3T-inducible genes included known Detoxication and antioxidative enzymes. Unexpected clusters included genes for chaperones, protein trafficking, ubiquitin/26 S proteasome subunits, and signaling molecules. Gene expression patterns in keap1-nrf2 double knockout mice were similar to those in nrf2-single knockout mice. D3T also led to nrf2-dependent repression of 31 genes at 24 h; principally genes related to cholesterol/lipid biosynthesis. Collectively, D3T increases the expression of genes through the Keap1-Nrf2 signaling pathway that directly detoxify toxins and generate essential cofactors such as glutathione and reducing equivalents. Induction ofnrf2-dependent genes involved in the recognition and repair/removal of damaged proteins expands the role of this pathway beyond primary control of electrophilic and oxidative stresses into secondary protective actions that enhance cell survival.

  • chemoprevention by inducers of carcinogen Detoxication enzymes
    Environmental Health Perspectives, 1997
    Co-Authors: Thomas W. Kensler
    Abstract:

    One of the major mechanisms of chemical protection against carcinogenesis, mutagenesis, and other forms of toxicity mediated by electrophiles is the induction of enzymes involved in their metabolism, particularly phase 2 enzymes such as glutathione S-transferases (GSTs), uridine diphosphate-glucuronosyltransferases, and NAD(P)H:quinone reductase. Furthermore, induction of phase 2 enzymes appears to be a sufficient condition for obtaining chemoprevention and can be achieved in many target tissues by administering any of a diverse array of naturally occurring and synthetic chemical agents. One class of chemopreventive agents, 1,2-dithiole-3-thiones, was developed on the basis of their potent activity in rodent tissues as inducers of GSTs. A substituted dithiolethione, oltipraz [4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione], is an effective inhibitor of aflatoxin B1-mediated hepatocarcinogenesis in the rat. Oltipraz produces dramatic decreases in the levels of aflatoxin-DNA adducts in the liver as well as in the urinary levels of the depurination product aflatoxin-N7-guanine. Corresponding increases are seen in the biliary elimination of aflatoxin-glutathione conjugates. Administration of oltipraz results in 3- to 4-fold increases in hepatic cytosolic GST activities and mRNA levels for some alpha, mu and pi isoforms. Nuclear run-on assays have indicated that oltipraz treatment elevates rates of transcription of some GST subunits. In the rat, induction of phase 2 enzymes by oltipraz is mediated, at least in part, through the antioxidant response element in the 5' flanking region of these genes. Although oltipraz has a very short plasma half-life, elevations in the levels of some GST isoforms can persist up to 1 week after dosing with oltipraz. Concordantly, intermittent dosing schedules (i.e., once a week) are nearly as effective as daily interventions for inhibition of aflatoxin-mediated hepatic tumorigenesis. The protective efficacy of daily and weekly administration of oltipraz to people in Qidong, People's Republic of China, who are at high risk for aflatoxin exposure and subsequent development of hepetocellular carcinoma, is currently under evaluation.

Stephan Pflugmacher - One of the best experts on this subject based on the ideXlab platform.

  • effects of 3 chlorobiphenyl on photosynthetic oxygen production glutathione content and Detoxication enzymes in the aquatic macrophyte ceratophyllum demersum
    Chemosphere, 2005
    Co-Authors: Mirta L Menone, Stephan Pflugmacher
    Abstract:

    Abstract Organic contaminants of environmental concern such as polychlorinated biphenyls have dispersed widely throughout the ecosystems and accumulate in living organisms, and a variety of adverse biological effects have been reported. In this study, we investigated the effects of 3-chlorobiphenyl in the aquatic macrophyte Ceratophyllum demersum and the capacity of its Detoxication system. After 24 h of exposure to various concentrations of 3-chlorobiphenyl, the total glutathione content (tGSH) was determined and the dose–response curves for glutathione reductase (GR) and microsomal/cytosolic glutathione S -transferases (m- and c-GSTs, respectively) were established. C. demersum showed a decrease of photosynthesis after exposure to 3-chlorobiphenyl, although only significantly at 5 μg l −1 . At 0.005 and 0.05 μg l −1 the GR, m-GST and c-GST activities were significantly increased and concomitantly a non-significant effect on total GSH was observed. At 0.5 μg l −1 , GR as well as c-GST were still significantly induced, while at 5 μg l −1 none of the enzymes were activated. These results show that Detoxication through glutathione conjugation takes place at low concentrations of 3-chlorobiphenyl, while concentrations in the order of parts per billion cause the inactivation of the enzymatic systems evaluated, enough to place C. demersum in an important physiological stress condition.

  • comparative effects and metabolism of two microcystins and nodularin in the brine shrimp artemia salina
    Aquatic Toxicology, 2003
    Co-Authors: Kenneth A Beattie, Claudia Wiegand, Christian E W Steinberg, Geoffrey A Codd, Judith Ressler, Eberhard Krause, Stephan Pflugmacher
    Abstract:

    The toxicity and metabolism of the cyanobacterial toxins microcystin-LR (MCLR), Dhb-microcystin-HtyR and nodularin were investigated in the cysts, nauplii and adults of the brine shrimp Artemia salina. The presence of the phase II Detoxication system glutathione S-transferase (sGST) in these stages was shown using different substrates. Exposure of adult A. salina to the toxins led to an elevation of GST activity in vivo. All three toxins were conjugated to glutathione via GST, which has been shown as an initial step of microcystin and nodularin Detoxication.

  • effects of the cyanobacterial toxin microcystin lr on Detoxication enzymes in aquatic plants
    Environmental Toxicology, 1999
    Co-Authors: Stephan Pflugmacher, Geoffrey A Codd, Christian E W Steinberg
    Abstract:

    The enrichment of water bodies with plant nutrients often results in mass growths of cyanobacteria which can produce a range of toxins. Cyanobacterial toxins have adverse effects on fish, birds, and mammals, and are being increasingly recognized as animal and human health hazards. The effects of cyanobacterial toxins on plants, particularly aquatic macrophytes, are little understood. The uptake of microcystin-LR (MC-LR) by Ceratophyllum demersum was detected with approximately 11.2% of the applied 14C-labelled microcystin being taken up after 7 days of exposure. The effects of various concentrations of this toxin on the Detoxication enzyme glutathione S-transferase (microsomal and soluble forms) were investigated. Microsomal glutathione S-transferase activity was increased in C. demersum exposed to concentrations of MC-LR above 0.12 μg/L, but reduced at concentrations above 1.0 μg/L, whereas soluble glutathione S-transferase activity was increased by exposure to MC-LR concentrations above 0.5 μg/L. No reduction of soluble GST activity was observed. The activity of both microsomal and soluble GST systems, freshly prepared from a range of plants, was inhibited in the presence of 0.5 μg/L MC-LR. The results indicate a Detoxication pathway for MC-LR in aquatic plants. ©1999 John Wiley & Sons, Inc. Environ Toxicol 14: 111–115, 1999

  • uptake and effects of microcystin lr on Detoxication enzymes of early life stages of the zebra fish danio rerio
    Environmental Toxicology, 1999
    Co-Authors: Claudia Wiegand, Stephan Pflugmacher, Christian E W Steinberg, Axel Oberemm, Nanke Meems, Kenneth A Beattie, Geoffrey A Codd
    Abstract:

    The effects of cyanotoxins on fish have been studied mainly in adults, rather than in early life stages which could be more sensitive or, in view of their immobility, more readily affected. The uptake of microcystin-LR by different early life stages of the zebra fish (Danio rerio) was investigated using 14C-labelled microcystin-LR. The effects on the activity of the Detoxication enzymes, microsomal and soluble glutathione S-transferases (GST), and glutathione peroxidase (GP-X) were examined. There was a detectable uptake of microcystin from the first day of embryonic development up to 5 day old larvae. On average, an absorption of 0.5 ng microcystin for eggs and eleuthero-embryos was calculated over the entire exposure time. Because of the differences in volume of the eggs and eleuthero-embryos, there was an increase in the microcystin-LR concentration between these stages. In the eggs, approximately 25% of the medium concentration was found, and in eleuthero-embryos an equilibrium between fish and medium was reached. The activity of the Detoxication enzymes differed during ontogenesis, but the effects of activation and suppression of these enzymes were similar at all stages. Minor activation of the soluble GST was found and a marked activation of GP-X was evident. The reaction of the microsomal GST was not so obvious. These results showed that there was an uptake of microcystin-LR by early life stages of the zebra fish and that the Detoxication system reacted to this toxin, possibly indicating the ability of the organism to metabolize microcystin-LR to a less harmful compound. Chronic toxic effects, such as reduction in growth, in such early life stages when organogenesis is not finished and hence the microcystin-LR affects not one single target organ but the whole organism, might be due to the increased energy demand of these Detoxication processes. ©1999 John Wiley & Sons, Inc. Environ Toxicol 14: 89–95, 1999

  • effects of the cyanobacterial toxin microcystin lr on Detoxication enzymes in aquatic plants
    Environmental Toxicology, 1999
    Co-Authors: Stephan Pflugmacher, Geoffrey A Codd, Christian E W Steinberg
    Abstract:

    The enrichment of water bodies with plant nutrients often results in mass growths of cyanobacteria which can produce a range of toxins. Cyanobacterial toxins have adverse effects on fish, birds, and mammals, and are being increasingly recognized as animal and human health hazards. The effects of cyanobacterial toxins on plants, particularly aquatic macrophytes, are little understood. The uptake of microcystin-LR (MC-LR) by Ceratophyllum demersum was detected with approximately 11.2% of the applied 14C-labelled microcystin being taken up after 7 days of exposure. The effects of various concentrations of this toxin on the Detoxication enzyme glutathione S-transferase (microsomal and soluble forms) were investigated. Microsomal glutathione S-transferase activity was increased in C. demersum exposed to concentrations of MC-LR above 0.12 μg/L, but reduced at concentrations above 1.0 μg/L, whereas soluble glutathione S-transferase activity was increased by exposure to MC-LR concentrations above 0.5 μg/L. No reduction of soluble GST activity was observed. The activity of both microsomal and soluble GST systems, freshly prepared from a range of plants, was inhibited in the presence of 0.5 μg/L MC-LR. The results indicate a Detoxication pathway for MC-LR in aquatic plants. ©1999 John Wiley & Sons, Inc. Environ Toxicol 14: 111–115, 1999

Christian E W Steinberg - One of the best experts on this subject based on the ideXlab platform.

  • comparative effects and metabolism of two microcystins and nodularin in the brine shrimp artemia salina
    Aquatic Toxicology, 2003
    Co-Authors: Kenneth A Beattie, Claudia Wiegand, Christian E W Steinberg, Geoffrey A Codd, Judith Ressler, Eberhard Krause, Stephan Pflugmacher
    Abstract:

    The toxicity and metabolism of the cyanobacterial toxins microcystin-LR (MCLR), Dhb-microcystin-HtyR and nodularin were investigated in the cysts, nauplii and adults of the brine shrimp Artemia salina. The presence of the phase II Detoxication system glutathione S-transferase (sGST) in these stages was shown using different substrates. Exposure of adult A. salina to the toxins led to an elevation of GST activity in vivo. All three toxins were conjugated to glutathione via GST, which has been shown as an initial step of microcystin and nodularin Detoxication.

  • effects of the cyanobacterial toxin microcystin lr on Detoxication enzymes in aquatic plants
    Environmental Toxicology, 1999
    Co-Authors: Stephan Pflugmacher, Geoffrey A Codd, Christian E W Steinberg
    Abstract:

    The enrichment of water bodies with plant nutrients often results in mass growths of cyanobacteria which can produce a range of toxins. Cyanobacterial toxins have adverse effects on fish, birds, and mammals, and are being increasingly recognized as animal and human health hazards. The effects of cyanobacterial toxins on plants, particularly aquatic macrophytes, are little understood. The uptake of microcystin-LR (MC-LR) by Ceratophyllum demersum was detected with approximately 11.2% of the applied 14C-labelled microcystin being taken up after 7 days of exposure. The effects of various concentrations of this toxin on the Detoxication enzyme glutathione S-transferase (microsomal and soluble forms) were investigated. Microsomal glutathione S-transferase activity was increased in C. demersum exposed to concentrations of MC-LR above 0.12 μg/L, but reduced at concentrations above 1.0 μg/L, whereas soluble glutathione S-transferase activity was increased by exposure to MC-LR concentrations above 0.5 μg/L. No reduction of soluble GST activity was observed. The activity of both microsomal and soluble GST systems, freshly prepared from a range of plants, was inhibited in the presence of 0.5 μg/L MC-LR. The results indicate a Detoxication pathway for MC-LR in aquatic plants. ©1999 John Wiley & Sons, Inc. Environ Toxicol 14: 111–115, 1999

  • uptake and effects of microcystin lr on Detoxication enzymes of early life stages of the zebra fish danio rerio
    Environmental Toxicology, 1999
    Co-Authors: Claudia Wiegand, Stephan Pflugmacher, Christian E W Steinberg, Axel Oberemm, Nanke Meems, Kenneth A Beattie, Geoffrey A Codd
    Abstract:

    The effects of cyanotoxins on fish have been studied mainly in adults, rather than in early life stages which could be more sensitive or, in view of their immobility, more readily affected. The uptake of microcystin-LR by different early life stages of the zebra fish (Danio rerio) was investigated using 14C-labelled microcystin-LR. The effects on the activity of the Detoxication enzymes, microsomal and soluble glutathione S-transferases (GST), and glutathione peroxidase (GP-X) were examined. There was a detectable uptake of microcystin from the first day of embryonic development up to 5 day old larvae. On average, an absorption of 0.5 ng microcystin for eggs and eleuthero-embryos was calculated over the entire exposure time. Because of the differences in volume of the eggs and eleuthero-embryos, there was an increase in the microcystin-LR concentration between these stages. In the eggs, approximately 25% of the medium concentration was found, and in eleuthero-embryos an equilibrium between fish and medium was reached. The activity of the Detoxication enzymes differed during ontogenesis, but the effects of activation and suppression of these enzymes were similar at all stages. Minor activation of the soluble GST was found and a marked activation of GP-X was evident. The reaction of the microsomal GST was not so obvious. These results showed that there was an uptake of microcystin-LR by early life stages of the zebra fish and that the Detoxication system reacted to this toxin, possibly indicating the ability of the organism to metabolize microcystin-LR to a less harmful compound. Chronic toxic effects, such as reduction in growth, in such early life stages when organogenesis is not finished and hence the microcystin-LR affects not one single target organ but the whole organism, might be due to the increased energy demand of these Detoxication processes. ©1999 John Wiley & Sons, Inc. Environ Toxicol 14: 89–95, 1999

  • effects of the cyanobacterial toxin microcystin lr on Detoxication enzymes in aquatic plants
    Environmental Toxicology, 1999
    Co-Authors: Stephan Pflugmacher, Geoffrey A Codd, Christian E W Steinberg
    Abstract:

    The enrichment of water bodies with plant nutrients often results in mass growths of cyanobacteria which can produce a range of toxins. Cyanobacterial toxins have adverse effects on fish, birds, and mammals, and are being increasingly recognized as animal and human health hazards. The effects of cyanobacterial toxins on plants, particularly aquatic macrophytes, are little understood. The uptake of microcystin-LR (MC-LR) by Ceratophyllum demersum was detected with approximately 11.2% of the applied 14C-labelled microcystin being taken up after 7 days of exposure. The effects of various concentrations of this toxin on the Detoxication enzyme glutathione S-transferase (microsomal and soluble forms) were investigated. Microsomal glutathione S-transferase activity was increased in C. demersum exposed to concentrations of MC-LR above 0.12 μg/L, but reduced at concentrations above 1.0 μg/L, whereas soluble glutathione S-transferase activity was increased by exposure to MC-LR concentrations above 0.5 μg/L. No reduction of soluble GST activity was observed. The activity of both microsomal and soluble GST systems, freshly prepared from a range of plants, was inhibited in the presence of 0.5 μg/L MC-LR. The results indicate a Detoxication pathway for MC-LR in aquatic plants. ©1999 John Wiley & Sons, Inc. Environ Toxicol 14: 111–115, 1999

Clement E. Furlong - One of the best experts on this subject based on the ideXlab platform.

  • Paraoxonase (PON1) and Detoxication of Nerve Agents
    Handbook of Toxicology of Chemical Warfare Agents, 2015
    Co-Authors: Lucio G. Costa, Toby B. Cole, Clement E. Furlong
    Abstract:

    Paraoxonase (PON1) is a serum and liver enzyme that can hydrolyze in vitro a number of organophosphorus (OP) compounds, including the active metabolites of specific OP insecticides, and certain OP nerve agents such as sarin and soman. PON1 presents several genetic polymorphisms that influence its ability to hydrolyze OPs as well as its level of expression. Studies using animals, including transgenic mice, have shown that PON1 modulates the in vivo acute toxicity of certain OPs, particularly chlorpyrifos oxon and diazoxon. In contrast, because of its low catalytic efficiency toward paraoxon, PON1 does not influence the acute toxicity of this OP in vivo. The catalytic efficiency of PON1 toward nerve agents is similarly low, although some studies have shown that administration of exogenous PON1 can protect against the toxicity of soman and sarin. For use as catalytic bioscavengers, recombinant engineered PON1s need to be developed with an enhanced catalytic efficiency toward nerve agents. Such PON1s would be excellent candidates for prophylactic and therapeutic applications in case of OP poisoning. A parallel strategy would be that of identifying and studying agents that would increase levels of endogenous PON1.

  • Paraoxonase 1 (PON1) status and substrate hydrolysis
    Toxicology and applied pharmacology, 2008
    Co-Authors: Rebecca J Richter, Gail P Jarvik, Clement E. Furlong
    Abstract:

    Paraoxonase 1 (PON1) hydrolyzes a number of organophosphorus (OP) compounds including insecticides and nerve agents. The in vivo efficacy of PON1 to protect against a specific OP exposure depends on the catalytic efficiency of hydrolysis. The Q192R polymorphism affects the catalytic efficiency of hydrolysis of some substrates and not others. While PON1R192 hydrolyzes paraoxon approximately 9-times as efficiently as PON1Q192, the efficiency is insufficient to provide in vivo protection against paraoxon/parathion exposure. The two PON1192 alloforms have nearly equivalent but higher catalytic efficiencies for hydrolyzing diazoxon (DZO) and provide equivalent in vivo protection against DZO exposures. On the other hand, PON1R192 is significantly more efficient in hydrolyzing chlorpyrifos oxon (CPO) than PON1Q192 and provides better protection against CPO exposure. Thus, for some exposures it is only the level of plasma PON1 that is important, whereas for others it is both plasma level and the PON1192 alloform(s) present in plasma that are important. In no case is the plasma level of PON1 unimportant, provided that the catalytic efficiency is sufficient to protect against the exposure. Two-substrate enzyme assay/analysis protocols that reveal both PON1 plasma levels and PON1192 phenotype (QQ; QR; RR) are designed to optimize the separation of PON1192 phenotypes; however, they have not been optimized for evaluating in vivo rates of OP Detoxication. This study describes the adaptation of a non-OP, two-substrate determination of PON1 status to the conversion of the PON1 status data to physiologically relevant rates of DZO and CPO Detoxication. Conversion factors were generated for rates of hydrolysis of different substrates.

  • genetic variability in the cytochrome p450 paraoxonase 1 pon1 pathway for Detoxication of organophosphorus compounds
    Journal of Biochemical and Molecular Toxicology, 2007
    Co-Authors: Clement E. Furlong
    Abstract:

    Detoxication of organophosphorus (OP) compounds is affected by genetic and environmental modulation of a number of enzymes involved in the process. For organophosphorothioate insecticides, different P450 isozymes and variants carry out two reactions that have quite different consequences; (1) they bioactivate their parent compounds to highly toxic oxon forms that are many times more toxic than the parent compounds, and (2) concurrently, they dearylate the parent OP compounds, generating much less toxic metabolites. The ratios at which these different P450s carry out bioactivation versus dearylation differ among the P450 isozymes. The Detoxication of the oxon forms of diazinon and chlorpyrifos is achieved by hydrolysis to the respective aromatic alcohols and diethyl phosphates primarily by paraoxonase 1 (PON1), a plasma enzyme tightly associated with high-density lipoprotein particles and also found in liver. Stoichiometric binding to other targets also contributes to the Detoxication of these oxons. PON1 is polymorphically distributed in human populations with an amino acid substitution (Gln/Arg) at position 192 of this 354-amino acid protein (the initiator Met residue is cleaved on maturation) that determines the catalytic efficiency of hydrolysis of some substrates. In addition to the variable catalytic efficiency determined by the position 192 amino acid, protein levels of PON1 vary by as much as 15-fold among individuals with the same PON1192 genotype (Q/Q; Q/R; R/R). The generation of PON1 null mice and transgenic mice, expressing each of the human PON1192 alloforms in place of mouse PON1, has allowed for the examination of the physiological function of the PON1192 alloforms in OP Detoxication. Sensitivity to diazoxon exposure is primarily determined by the plasma level of PON1, whereas for chlorpyrifos oxon exposure, both the plasma PON1 level and the position 192 amino acid are important—PON1R192 is more efficient in inactivating chlorpyrifos oxon than is PON1Q192. The availability of PON1 null mice provides an opportunity to examine the contribution of other enzymes in the OP Detoxication pathways without PON1 interference. © 2007 Wiley Periodicals, Inc. J Biochem Mol Toxicol 21:197–205, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20181