Decreased uroporphyrinogen decarboxylase activity in ‘experimental symptomatic porphyria’
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Uroporphyrinogen III decarboxylase
Hexachlorobenzene
Decarboxylation
Chronic hepatic
Uroporphyrinogen III decarboxylase
Hexachlorobenzene
Chronic hepatic
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Abstract Uroporphyrinogen decarboxylase is an essential enzyme in all organisms and functions in the heme biosynthetic pathway, catalyzing the decarboxylation of the four acetate groups of uroporphyrinogen to form coproporphyrinogen. This work examines whether the four sequential decarboxylations occur at the same active site, and explores whether hexachlorobenzene‐induced porphyria affects the behavior of the enzyme. For this purpose, kinetic competition studies were done with mixtures of uroporphyrinogen III and pentacarboxyporphyrinogen III. With the enzyme from normal rats, a constant velocity was obtained with all the mixtures, indicating that uroporphyrinogen and pentacarboxy‐porphyrinogen react at the same active site, i.e. the first and fourth decarboxylations occur at the same site. In contrast, in experiments with enzyme from rats with hexachlorobenzene‐induced porphyria, the total rate for mixtures was always lower than the reference rate; and a curve with a deep minimum was obtained, indicating that the two reactions occur at functionally different sites, but with cross‐inhibition. This suggests that the modifications induced in the enzyme by hexachlorobenzene cause the two active sites to become nonequivalent and functionally different. The question is discussed how the hexachlorobenzene treatment may produce this abnormal kinetic behavior, and alternative hypotheses are considered. © 2005 Wiley Periodicals, Inc. J Biochem Mol Toxicol 19:19–24, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20055
Hexachlorobenzene
Uroporphyrinogen III decarboxylase
Decarboxylation
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Uroporphyrinogen III decarboxylase
Hexachlorobenzene
Decarboxylation
Chronic hepatic
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The activity of the enzyme uroporphyrinogen decarboxylase was determined in the liver and the kidneys of C57BL/6 mice and Wistar albino rats with chronic hexachlorobenzene intoxication and the amount of the deposited uroporphyrin was measured in the both organs. In the control animals the activity of hepatic uroporphyrinogen decarboxylase was several times higher than the renal one. The administration of hexachlorobenzene led to an inhibition of the enzyme activity, which was equally expressed (about 2.5 times) in the liver and kidneys of the both species. The accumulation of uroporphyrin was more pronounced in the hepatic tissue than in the kidneys (about 9 times in mice and 5 times in rats on average). Taking into consideration the much higher uroporphyrin accumulation in the liver, the more active haem biosynthesis in this organ, as well as its larger size, one could accept that the predominant part of the urinary porphyrins in hexachlorobenzene porphyria has a hepatic and not a renal origin.
Hexachlorobenzene
Uroporphyrinogen III decarboxylase
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Effects of hexachlorobenzene (HCB) and its sulfur-containing metabolites on the heme metabolic enzymes in rat liver were investigated. A single injection of HCB caused the increase in activities of δ-aminolevulinic acid (ALA) synthetase and heme oxygenase, and contents of cytochrome P-450 and total heme. After a single injection of pentachlorothioanisol (PCTA) or pentachlorophenyl methyl sulfore (PCPSO2Me), ALA synthetase activity was enhanced. Heme oxygenase activity was increased by PCPSO2 Me treatment. Cytochrome P-450 and total heme contents were increased by PCPSO2Me or 1, 4-bis(methylthio)tetrachlorobenzene (MTTCB). When HCB was injected once daily for 5 weeks, a marked increase in ALA synthetase activity, a significant decrease in ALA dehydratase, almost complete inhibition of uroporphyrinogen decarboxylase activity, and an increased excretion of total porphyrin in the urine were shown. After chronic treatment with its sulfur-containing compounds, PCPSO2 Me and MTTCB produced a significant increase in ALA synthetase activity. However, activities of ALA dehydratase and uroporphyrinogen decarboxylase, and excretion of total porphyrin in the urine were unaltered. At this time, the concentrations of the corresponding sulfur-containing compound and related metabolite(s) in blood, liver and kidney were nearly the same as those observed in HCB-treated rats. It is suggested that PCPSO2 Me and MTTCB could induce the hepatic ALA synthetase, but these metabolites, and also PCTA, were not able to induce the porphyria in female rats, and the induction of porphyria by HCB is not attribuable to the action of its sulfur-containing compound.
Hexachlorobenzene
Liver enzyme
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Hexachlorobenzene
Uroporphyrinogen III decarboxylase
Porphyria cutanea tarda
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During hexachlorobenzene feeding of rats the following biochemical signs of a chronic hepatic porphyria developed: porphyrinuria with increase of uro- and hexacarboxyporphyrin, hepatic prophyrin accumulation of uro- and heptacarboxyporphyrin and a diminished activity of uroporphyrinogen decarboxylase in the liver, but nut in the red cells. During the 5.3 days of the intoxication the behaviour of metabolite constellation and enzyme activities was inverse. Hexachlorobenzene porphyria in rats is a pathobiochemical model of chronic hepatic prophyria, which in man becomes clinically manifest as porphyria cutanea tarda.
Uroporphyrinogen III decarboxylase
Hexachlorobenzene
Porphyria cutanea tarda
Chronic hepatic
Liver enzyme
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S ummary . Chronic feeding of hexachlorobenzene to rats increases the levels of certain hepatic haemoproteins prior to the onset of hepatic porphyria. The onset of hepatic porphyria is slow and only water soluble porphyrins accumulate in the livers. The accumulation of hexachlorobenzene by the liver is progressive but no direct correlation exists between the amount of HCB in the liver, the extent of hepatic porphyria and the changes in haemoprotein concentration. Similarities between experimental hepatic porphyria induced by hexachlorobenzene and those seen in human symptomatic porphyria are presented and emphasize the usefulness of the hexachlorobenzene model with which to study the human disease.
Hexachlorobenzene
Chronic hepatic
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Oral administration of a commercial PCB mixture to chickens caused a hepatic-type porphyria characterized by hepatic accumulation and urinary excretion of uroporphyrin. To clarify the mechanism of the porphyrinogenic activity of these PCBs, we studied the structural requirement of synthetic PCB for porphyrinogenic activities by using the cultured chick embryo liver cells and examined the relationship between induction of delta-aminolevulinic acid (ALA) synthetase and inhibition of uroporphyrinogen decarboxylase. We established that the porphyrinogenic effect of PCBs exhibits a sharply defined structure-activity relationship in that only 3,4,3',4'-tetrachlorobiphenyl and 3,4,5,3',4',5'-hexachlorobiphenyl produced a marked accumulation of uroporphyrin. We also demonstrated that in ALA-supplemented cultures, these same compounds lead to accumulation of a large amount of uroporphyrin III, whereas with other PCBs, which were weak inducers of porphyrin synthesis, the accumulated porphyrin was mostly protoporphyrin. was mostly protoporphyrin. Kinetic studies of the sequential decarboxylation of uroporphyrinogen with purified uroporphyrinogen decarboxylase were performed. The 3,4,3',4'-tetrachlorobiphenyl and 3,4,5,3',4',5'-hexachlorobiphenyl strongly inhibit uroporphyrinogen decarboxylase directly at two steps, i.e. first in the formation of hexacarboxylic porphyrinogen III from heptacarboxylic porphyrinogen III and second in the formation of heptacarboxylic porphyrinogen III from uroporphyrinogen III. The results confirmed that porphyrinogenic PCBs primarily inhibit uroporphyrinogen decarboxylase, leading to a depletion of heme as a result of which synthesis of ALA synthetase increased.
Uroporphyrinogen III decarboxylase
Decarboxylation
Hexachlorobenzene
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