The relation between the oxidative biotransformation of hexachlorobenzene and its porphyrinogenic activity

Ommen, Ben van; Hendriks, W.L.; Bessems, Jos; Geesink, G.H.; Müller, Franz; Bladeren, P.J. van

doi:10.1016/0041-008x(89)90299-8

Cited by 39 publications

(14 citation statements)

References 28 publications

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“…Some evidence for this hypothesis can be derived from literature data which demonstrate that hydroxylation of hexachlorobenzene and of pentachlorophenol at halogenated positions was better catalyzed by cytochrome P450 IIIAl than by other cytochromes P450 [21].…”

Section: Discussionmentioning

confidence: 99%

Reaction pathways for biodehalogenation of fluorinated anilines

Rietjens

Tyrakowska

Veeger

et al. 1990

European Journal of Biochemistry

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Pathways for biodehalogenation of fluorinated aniline derivatives were investigated. Microsomal NADPHdependent dehalogenation of fluoroanilines was shown to proceed by three different reaction pathways. The first route appeared to result in monooxygenation at a fluorinated position and release of the fluorine atom as a fluoride anion. The primary additional reaction product formed is the reactive quinoneimine, not the 4-hydroxyaniline. In NADPH-containing microsomal systems with 4-fluoro-substituted anilines, formation of the 4-hydroxyaniline derivative is observed because NADPH chemically reduces this quinoneimine metabolite. A second pathway for dehalogenation proceeds by protein binding of a fluoro-containing (semi)quinoneimine metabolite, the formation of which may result from the mono-oxygenase reaction (pathway 1) and/or from (re)oxidation of a hydroxyaniline metabolite by superoxide anion radicals produced by the microsomal system. This latter reaction pathway becomes more important with increasing number of fluoro-substituents in the fluoroaniline derivative. The higher ratio of fluoride anion formed to 4-hydroxyaniline derivative detected in incubations with liver microsomes from dexamethasone-treated rats, as compared to incubations with liver microsomes from control rats, can in part be explained by the higher production of superoxide anion radicals observed in the dexamethasone systems.The third mechanism was shown to proceed by formation of a hydroxylated metabolite that loses fluoride anion upon exposure to oxygen. The reactive intermediate formed upon oxygen exposure might be the semiquinoneimine which loses its fluorine atom as a fluoride anion upon dimerization or polymerization and/or protein binding. The fluorohydroxyanilines, in which the hydroxyl group is ortho or para with respect to the fluoro substituent, appear especially to be highly unstable and lose fluoride anion in the presence of oxygen.Finally, it is concluded that all three pathways for dehalogenation of fluorinated aniline derivatives are bioactivation pathways. The reactivity of the (semi)quinoneimines formed in these reactions is dependent on their substitution pattern and increases with increasing number of fluoro-substituents. Therefore, bioactivation for a series of fluorinated aniline derivatives, can be expected to vary with the substitution pattern and to increase with increasing number of halogen substituents.The accumulation of halogen-containing aliphatic and aromatic compounds is a major factor adding to environmental pollution. The phenomenon originates from the widespread use of halogen-containing compounds in industry, commerce and medicine and from the relatively high persistence of these chemicals [I, 21. In addition, these halogencontaining compounds may give rise to a variety of toxic effects caused by either the bioaccumulation of poorly metabolized compounds and/or by their biotransformation to reactive intermediates [2]. One of the reactions resulting in formation of reactive intermediates could be dehaloge...

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Section: Discussionmentioning

confidence: 99%

Reaction pathways for biodehalogenation of fluorinated anilines

Rietjens

Tyrakowska

Veeger

et al. 1990

European Journal of Biochemistry

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“…Conjugation to GSH by glutathion-s-transferase eventually leads to the formation of PCP-NAC, which is excreted via the urine (11). HCB can also be degraded by P450-catalyzed oxidative dehalogenation to PCP, TCHQ, and TCBQ (12). Under physiological conditions, TCHQ autoxidizes into its semiquinone radical and further into TCBQ (13).…”

Section: Introductionmentioning

confidence: 98%

Immunomodulatory Effects of Tetrachlorobenzoquinone, a Reactive Metabolite of Hexachlorobenzene

Ezendam

Vissers

Bleumink

et al. 2003

Chem. Res. Toxicol.

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Hexachlorobenzene (HCB) is an environmental pollutant that causes autoimmune-like effects in humans and rats. It is not completely clear whether T cells are involved and, if so, how they are stimulated after oral exposure to HCB. HCB as a rather inert chemical is not likely to bind covalently to macromolecules. The oxidative metabolite of HCB, tetrachlorobenzoquinone (TCBQ), which is in a redox equilibrium with tetrachlorohydroquinone (TCHQ), can bind to macromolecules, hence may form hapten-carrier complexes in vivo. We have assessed in the reporter antigen-popliteal lymph node assay whether HCB or TCHQ and TCBQ are able to induce a 2,4,6-trinitrophenyl (TNP) specific IgG1 response to the T cell-independent antigen TNP-Ficoll, which is indicative of neoantigen specific T cell help. To this end, these compounds and silica were injected into the footpad of Balb/c mice. Silica was included as an inert model compound, which causes autoimmune-like effects by activating macrophages. Seven days later, cell number and TNP specific antibody-secreting cells (ASC) in the popliteal lymph node (PLN) were determined. Furthermore, a secondary PLNA was performed to find out if TCHQ was capable of eliciting a memory response. Silica, TCHQ, and TCBQ, but not HCB, increased PLN cellularity and the number of IgM-producing ASC by ELISPOT. Both oxidative metabolites were able to induce the formation of germinal centers as assessed by immunohistochemistry and an IgG1 response to TNP-Ficoll. In the secondary PLNA, only mice primed with TCHQ and challenged with TCHQ together with TNP-Ficoll showed a significant increase in TNP specific IgG1 ASC. Present data show that TCHQ and TCBQ are capable of inducing neoantigen specific T cell help and that TCHQ can induce a compound specific memory response.

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“…9,16,17 Hexachlorobenzene alone is not porphyrinogenic within the same time frame. 16 In rats, hexachlorobenzene or polychlorinated biphenyl appears to require extended time periods of exposure to produce uroporphyria, [21][22][23][24][25][26][27] and mice fed purified polychlorinated biphenyl isomers required 13 weeks to develop uroporphyria. 28 It is not known whether polychlorinated biphenyls can cause experimental uroporphyria within a short time frame in porphyria-susceptible mice with the Uro-Dϩ/Ϫ genotype.…”

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confidence: 99%

Uroporphyria in the uroporphyrinogen decarboxylase-deficient mouse: Interplay with siderosis and polychlorinated biphenyl exposure

2002

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Several methods have been used to develop rodent models with the hepatic manifestations of porphyria cutanea tarda (PCT). Acute iron administration or mutations of the hemochromatosis gene (Hfe) have been used to generate hepatic siderosis, a nearly uniform finding in PCT. Heterozygosity for a null mutation at the uroporphyrinogen decarboxylase (Uro-D؉/؊) locus has been developed to mimic familial PCT in humans. This study examines the interplay of these 2 genetic risk factors and their influence, alone and combined with polychlorinated-biphenyl exposure. Neither an Hfe-null mutation nor iron-dextran administration alone or in combination with polychlorinated biphenyl exposure was porphyrinogenic in a 3-week model using mice wild-type at the Uro-D locus. Homozygosity for an Hfe-null mutation significantly elevated hepatic iron but not to the extent seen with parenteral iron-dextran administration. Homozygosity for an Hfe-null mutation but not irondextran administration was porphyrinogenic in animals heterozygous for the Uro-D mutation. Polychlorinated biphenyls were also porphyrinogenic in these animals. Uroporphyria in Uro-D؉/؊ animals was exacerbated by combinations of the homozygous Hfe-null mutation and polychlorinated biphenyls and iron-dextran and polychlorinated biphenyls. In all cases in which uroporphyria developed, a greater degree of experimental uroporphyria was seen in female animals. All elevated hepatic uroporphyrin concentrations were accompanied by depressed uroporphyrinogen decarboxylase activity and the presence of a factor in cytosol that inhibits recombinant human uroporphyrinogen decarboxylase. In conclusion, the expression of the uroporphyric phenotype, dependent on the susceptibility imparted by a genetic mutation, provides a uniquely facile model for dissecting the molecular pathogenesis of the disease. (HEPATOLOGY 2002;36:805-811.) P orphyria cutanea tarda (PCT), the most common porphyric disorder of humans, 1,2 is characterized clinically by a photosensitive bullous dermatosis and a marked increase in urinary excretion of uroporphyrin and heptacarboxylporphyrin. The source of the excess porphyrin production responsible for these findings is the liver, in which the activity of uroporphyrinogen decarboxylase (URO-D) is markedly reduced. Heterozygosity for mutations at the URO-D locus (URO-Dϩ/Ϫ) can be detected in about one third of cases. 2 Hepatic siderosis is a nearly constant finding in PCT, and homozygosity for mutations of the hemochromatosis gene (HFE) can be found in approximately 20% of cases. [2][3][4] In addition to these 2 identified genetic factors, environmental influences such as alcohol abuse, hepatitis C virus, and exposure to medicinal estrogens have been implicated in the pathogenesis of PCT, 2 but the largest human outbreak of PCT followed exposure to halogenated aromatic hydrocarbons. 5,6 Numerous rodent models of PCT have been developed. These models, characterized by an increase in hepatic porphyrin concentration and depression of URO-D activity, have generally been...

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The relation between the oxidative biotransformation of hexachlorobenzene and its porphyrinogenic activity

Cited by 39 publications

References 28 publications

Reaction pathways for biodehalogenation of fluorinated anilines

Reaction pathways for biodehalogenation of fluorinated anilines

Immunomodulatory Effects of Tetrachlorobenzoquinone, a Reactive Metabolite of Hexachlorobenzene

Uroporphyria in the uroporphyrinogen decarboxylase-deficient mouse: Interplay with siderosis and polychlorinated biphenyl exposure

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