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Contribution to the elucidation of the mechanism of hepatic porphyria induced by hexachlorobenzene and related polyhalogenated hydrocarbons
No full textPolyhalogenated aromatic hydrocarbons are known to cause hepatic porphyria in man and in various species of animals. This disorder in porphyrin metabolism is attributed to a defect in the activity of the intermediary enzyme uroporphyrinogen decarboxylase in the heme biosynthetic parhway and leads to an accumulation (in the liver) and excretion (in urine and feces) of large amounts of mainly uroporphyrin. However, the mechanism underlying this block in the hepatic heme biosynthesis is not known.The present studies have been carried out to further elucidate the mechanism of action of polyhalogenated aromatic compounds (PHAs) on the hepatic heme biosynthesis. Hexachlorobenzene (HCB),. a member of this group of foreign chemicals, was used as a model compound in our investigations.Chapter 1 gives a review of literature data on those aspects of the toxicology, pharmacokinetics and biotransformation of PHAs that are relevant to explain their effects on the hepatic heme synthesis. Special emphasis is given to HCB.Chapter 2 describes the effects of pentachlorophenol (one of the main metabolites of HCB) on the induction of hepatic porphyria and mixed function oxygenases in female rats administered HCB. The porphyrinogenic effect of HCB was enhanced by simultaneous treatment with pentachlorophenol. whereas rats receiving pentachlorophenol alone developed no symptoms of hepatic porphyria. Pentachlorophenol showed a high affinity for membranes of the endoplasmic reticulum (see also Chapter 4) and it was found to destroy cyrochrome P-450 in vitro. From these results it is concluded that pentachlorophenol is not the metabolite that ultimately causes hepatic porphyria. However. pentachlorophenol may contribute indirectly to the porphyrinogenic action of HCB by stimulating the heme biosynthesis as a result of an accelerated breakdown of cytochrome P-450 heme. The concomitant increased production of heme exacerbates the porphyria caused by the defect of uroporphyrinogen decarboxylase.Chapter 3 deals with the effects of several compounds interfering with the biotransformation reactions of PHAs on the accumulation of porphyrins in primary cultures of chick embryo liver cells treated with PHAs. Pre-induction of the enzyme system involved in the biotransformation of PHAs markedly enhanced the porphyrinogenic effect of PHAs in chick embryo liver cells. Inhibition of the induction of δ-aminolevulinic acid synthase with increasing concentrations of hemin could not prevent PHA-induced porphyrin accumulation. inhibition of the mixed function oxygenase system or addition of elec trophile-trapping agents protected chick embryo liver cells against the porphyrinogenic effect of PHAs. A decrease of the level of intracellular glutathione with glutathione-depleting agents led to an enhancement of the cytotoxicity of PHAs in chick embryo liver cell cultures. It is suggested that a reactive intermediate, formed by biotransformation of the PHA, reacts with the catalytic SH-containing part of the uroporphyrinogen decarboxylating enzyme in the cytoplasm of the liver cells.Chapter 4 gives a report of the effects of combined administration of HCB with either phenobarbital or 3-methylcholanthrene on female rat liver. The results presented in this Chapter and in Chapter 2 show that HCB induces a pattern of hepatic mixed function oxygenases which shares characteristics of the enzyme pattern induced by both phenobarbital and 3-methylcholanthrene. Simultaneous treatment with HCB and phenobarbital, but not with HCB and 3-methylcholanthrene, markedly enhanced the porphyrinogenic effect of HCB in female rats. These results suggest a key role for the phenobarbital-inducible form of cytochrome(s) P-450 in the biotransformation of HCB and the induction of hepatic porphyria.Chapter 5 shows that HCB is metabolized in chick embryo liver cell cultures. The HCB-metabolites identified in chick embryo liver cell culture are the same as those found in HCB-treated rats. Since none of the major phenolic- and sulfur-containing metabolites of HCB were able to cause porphyrin accumulation in chick embryo liver cell culture, an unstable reactive intermediate capable of reacting with SH-groups of proteins is suspected to be responsible for the inhibition of uroporphyrinogen decarboxylase and the onset of hepatic porphyria. In liver cell cultures treated with [ 14C] HCB some radioactivity became irreversibly bound to cell protein. Addition of the monooxygenase- inhibitor piperonyl butoxide or ascorbic acid reduced the protein binding of 14C-metabolites. Based on the results, it appears that the rate of biotransformation of HCB has to be above a critical level before the enzyme uroporphyrinogen decarboxylase becomes inhibited and hepatic porphyria develops.In Chapter 6 a comparison is made of the effects of dietary antioxidants on the biotransformation and porphyrinogenic action of HCB in two strains of female rats, which differ in their susceptibility to HCB. Female Agus rats were much more susceptible to the porphyrinogenic effect of HCB than female rats of the Wistar strain. The following differences between the Wistar and Agus strains of rats in their responses to HCB were noticed: (1) HCB induced in Agus rats a higher mixed function oxygenase activity than in Wistar rats. In addition, the biotransformation rate of HCB appeared to be higher in the Agus rats. (2) Glutathione-S-transferase activity was less induced in HCB-treated Agus rats than in correspondingly treated Wistar rats. (3) Agus rats had significantly lower levels of glutathione in their livers than the Wistar rats. These differences may be responsible for the increased susceptibility of the Agus strain to the porphyrinogenic effect of HCB. Moreover, these findings support the hypothesis that binding of reactive intermediates of HCB biotransformation to functional SH-groups of uroporphyrinogen decarboxylase forms the key process in the disturbance of the hepatic heme biosynthesis. The observation that HCB was excreted in this experiment for almost 60% as sulfur- containing metabolites again confirmed the affinity of intermediate metabolic products of HCB for SH-groups.In contrast to the results obtained with primary chick embryo liver cell cultures (Chapter 3), dietary antioxidants could not protect against the porphyrinogenic effect of HCB in vivo. Some possible explanations for this discrepancy are given in the discussion of the final Chapter
The ultrastructure and renewal of the intestinal epithelium of the juvenile grasscarp, Ctenopharyngodon idella (Val.)
No full textAn Approach to elucidate the mechanism of hexachloro-benzene-induced hepatic porphyria, as a model for the hepatotoxicity of polyhalogenated aromatic compounds
No full textOccurrence of porphyrinogenic compounds as a hazard to consumer, industrial worker and wildlife
No full textAn Approach to elucidate the mechanism of hexachloro-benzene-induced hepatic porphyria, as a model for the hepatotoxicity of polyhalogenated aromatic compounds
No full text
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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