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At least 19 recordsLinked to original sources
PubMed1988

Uroporphyrin accumulation in cultured chick embryo hepatocytes: comparison of 2,3,7,8-tetrachlorodibenzo-p-dioxin and 3,4,3',4'-tetrachlorobiphenyl.

Uroporphyrin (URO) accumulation caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3,4,3',4'-tetrachlorobiphenyl (TCB) in cultured chick embryo hepatocytes was found to depend on the concentration of the added polyhalogenated aromatic compound, and on either the addition of 5-aminolevulinic acid or the induction of 5-aminolevulinic acid synthase. TCDD alone did not cause more than a slight increase in uroporphyrin, whereas TCB alone caused considerable uroporphyrin accumulation associated with increased 5-aminolevulinic acid synthase activity. However, in the presence of exogenous 5-aminolevulinic acid, TCDD was more potent than TCB in causing uroporphyrin accumulation. The concentrations of TCDD or TCB which maximally induced ethoxyresorufin deethylase activity, an indicator of induced cytochrome P450 activity, were lower than those required for maximal uroporphyrin accumulation. Furthermore, ethoxyresorufin deethylase activity was found to decline at concentrations of TCDD or TCB which caused maximum uroporphyrin accumulation. Pretreatment with 3-methylcholanthrene enhanced uroporphyrin accumulation, whereas addition of inhibitors of cytochrome P450 decreased uroporphyrin accumulation. Uroporphyrin accumulation occurred without a decrease in uroporphyrinogen decarboxylase activity, and was unrelated to the degree of conversion of the polyhalogenated aromatic compounds to water-soluble metabolites. Our results indicate that URO accumulation caused by TCDD and TCB requires two separate actions; (1) induction of cytochrome P450 which occurs at low concentrations of the halogenated chemicals, and (2) increased uroporphyrinogen oxidation which is catalyzed by the induced cytochrome P450 and which occurs at higher concentrations of the halogenated chemicals.

Animals↗
PubMed2003

Export of a heterologous cytochrome P450 (CYP105D1) in Escherichia coli is associated with periplasmic accumulation of uroporphyrin.

This report suggests an important physiological role of a CYP in the accumulation of uroporphyrin I arising from catalytic oxidative conversion of uroporphyrinogen I to uroporphyrin I in the periplasm of Escherichia coli cultured in the presence of 5-aminolevulinic acid. A structurally competent Streptomyces griseus CYP105D1 was expressed as an engineered, exportable form in aerobically grown E. coli. Its progressive induction in the presence of 5-aminolevulinic acid-supplemented medium was accompanied by an accumulation of a greater than 100-fold higher amount of uroporphyrin I in the periplasm relative to cells lacking CYP105D1. Expression of a cytoplasm-resident engineered CYP105D1 at a comparative level to the secreted form was far less effective in promoting porphyrin accumulation in the periplasm. Expression at a 10-fold molar excess over the exported CYP105D1 of another periplasmically exported hemoprotein, the globular core of cytochrome b5, did not substitute the role of the periplasmically localized CYP105D1 in promoting porphyrin production. This, therefore, eliminated the possibility that uroporphyrin accumulation is merely a result of increased hemoprotein synthesis. Moreover, in the strain that secreted CYP105D1, uroporphyrin production was considerably reduced by azole-based P450 inhibitors. Production of both holo-CYP105D1 and uroporphyrin was dependent upon 5-aminolevulinic acid, except that at higher concentrations this resulted in a decrease in uroporphyrin. This study suggests that the exported CYP105D1 oxidatively catalyzes periplasmic conversion of uroporphyrinogen I to uroporphyrin I in E. coli. The findings have significant implications in the ontogenesis of human uroporphyria-related diseases.

Aminolevulinic Acid↗
PubMed1993

Ferritin accumulation and uroporphyrin crystal formation in hepatocytes of C57BL/10 mice: a time-course study.

To establish the time-sequence relationship between ferritin accumulation and uroporphyrin crystal formation in livers of C57BL/10 mice, a biochemical, morphological and morphometrical study was performed. Uroporphyria was induced by the intraperitoneal administration of hexachlorobenzene plus iron dextran and of iron dextran alone. Uroporphyrin crystal formation started in hepatocytes of mice treated with hexachlorobenzene plus iron dextran at 2 weeks and in mice treated with iron dextran alone a 9 weeks. In the course of time, uroporphyrin crystals gradually increased in size. Uroporphyrin crystals were initially formed in hepatocytes in the periportal areas of the liver, in which also ferric iron staining was first detected. The amount and the distribution of the main storage form of iron in hepatocytes, ferritin, did not differ between the two treatment groups. Ferritin accumulation preceded the formation of uroporphyrin crystals in hepatocytes in both treatment groups. Moreover, uroporphyrin crystals were nearly always found close to ferritin iron. We conclude that uroporphyrin crystals are only formed in hepatocytes in which also iron (ferritin) accumulates. Hexachlorobenzene accelerates the effects of iron in porphyrin metabolism, but does not influence the accumulation of iron into the liver.

Animals↗
PubMed1996

Mechanistic studies on uroporphyrin I-induced photoinactivation of some heme-enzymes.

Aerobic and anaerobic studies have demonstrated that uroporphyrin I-induced inactivation of delta-aminolevulinic acid dehydratase, porphobilinogenase, deaminase and uroporphyrinogen decarboxylase was dependent on oxygen and mediated by reactive oxygen species. The mechanism of photoinactivation of those heme-enzymes from human erythrocytes by uroporphyrin I by u.v. light was investigated. Enzymes of the heme pathway were preincubated in the presence of specific scavengers for several reactive oxygen species and then exposed to uroporphyrin I and u.v. light. Upon exposure of the enzymes to the porphyrin under u.v. light, and in an aerobic atmosphere, the percentage of enzyme activities with respect to the corresponding controls were 50.2 +/- 5.1 (SD, n = 6), 25.3 +/- 3.0 (SD, n = 6), 25.9 +/- 2.8 (SD, n = 6) and 49.7 +/- 7.5 (SD, n = 8) for delta-aminolevulinic acid dehydratase, porphobilinogenase, deaminase and uroporphyrinogen decarboxylase, respectively. The presence of sodium azide, histidine or superoxide dismutase did not protect the enzymes against the effects of uroporphyrin I. However, both cysteine and potassium ferrycyanide prevented the enzyme photoinactivation induced by uroporphyrin I. In the presence of either catalase or GSH, the enzyme photoinactivation was lower. Ethanol, glucose and dimethylsulfoxide had no effect on enzyme activity, while ion chelators had variable effects. This study shows that the type II mechanism is not the predominant reaction mediating the uroporphyrin I effect and enzyme photoinactivation would involve an electron transfer. Hydrogen peroxide and hydroxyl radicals could possibly mediate the uroporphyrin I-induced enzyme photoinactivation.

Ammonia-Lyases↗
PubMed1991

Effective control of patients with porphyria cutanea tarda by measuring plasma uroporphyrin.

The clinical value of a very rapid spectrofluorometric method for the determination of plasma uroporphyrin levels was studied during follow-up of 122 patients with porphyria cutanea tarda (PCT). Four-hundred and eight measurements were carried out within a 3-year period. In active PCT plasma uroporphyrin varied between 15 and 448 nmol/l (normal 0-1.4). A high correlation was seen between elevated levels of uroporphyrin in the plasma and urine in new cases (r = 0.72, n = 23) and relapses (r = 0.92, n = 37). A parallel course between these variables was noted during the treatment of 31 patients. The correlation was less pronounced (r = 0.42) in remission, i.e. in those cases with urinary uroporphyrin levels lower than 240 nmol/24 h. However, only in nine of 249 measurements taken in remission did plasma uroporphyrin exceed 15 nmol/l. In six of these cases a biochemical relapse had occurred at the next follow-up measurement as judged by an increase of uroporphyrin in the urine. It is suggested that treatment of new cases and relapses should continue until plasma uroporphyrin drops under 10 nmol/l. Values between 15 and 23 nmol/l in individuals already treated raise the suspicion of relapse and should be rechecked in the near future. Retreatment is necessary when the levels exceed 23 nmol/l. The use of the method is recommended as a simple and effective way for monitoring the progress of patients with PCT.

Adult↗
PubMed1982

Uroporphyrin I stimulation of collagen biosynthesis in human skin fibroblasts. A unique dark effect of porphyrin.

Porphyria cutanea tarda and erythropoietic porphyria are disorders of heme synthesis that originate in the liver and bone marrow, respectively. Each is characterized by increased accumulation of uroporphyrin, I, by cutaneous photosensitivity, and in some patients by indurated plaques and scarring that resemble scleroderma. These scleroderma-like lesions occur in light-exposed and light-protected body areas. In these studies we evaluated the role of uroporphyrin I and of light in evoking the scleroderma-like cutaneous changes. Normal human skin fibroblasts were exposed to uroporphyrin I and to 400 nm radiation and the effect of these agents on collagen accumulation by the cells was determined. Radioactive tracer studies showed that uroporphyrin I caused a specific increase in the accumulation of newly synthesized collagen by fibroblast monolayer cultures, as verified by [(3)H]hydroxyproline and collagenase digestion assays. Collagen accumulation was stimulated 1.5- to 2.7-fold by uroporphyrin I, whereas noncollagenous protein accumulation was unchanged. The increased collagen accumulation was time and uroporphyrin I-concentration-dependent, and occurred both in the presence or absence of ultraviolet light exposure. Further studies demonstrated that the increased accumulation was not the result of decreased rates of collagen degradation nor was it due to changes in cell population growth parameters (generation times and saturation densities). No changes in morphology of the treated cells occurred. These studies indicate that porphyrins possess previously undemonstrated biological effects that are independent of their photosensitizing properties. This novel dark effect of uroporphyrin I may account for the sclerodermatous lesions seen in the skin of patients with porphyria cutanea tarda and erythropoietic porphyria.

Cells, Cultured↗
PubMed1991

Role of iron in the photosensitization by uroporphyrin.

The role of iron in the mechanism of photosensitivity due to uroporphyrin was investigated. There is frequently increased levels of Fe in the serum from patients with porphyria cutanea tarda, where the photosensitivity is due to uroporphyrin. It has been reported that H2O2 has a major role in the uroporphyrin induced photosensitivity. Hence we examined the hypothesis that Fe would catalyze the production of OH from H2O2 and the OH thus formed may have a significant role in the uroporphyrin photosensitivity. This was examined by studying the effects of the Fe chelating compound deferoxamine in an in vitro system. Our results show that deferoxamine inhibited the uroporphyrin photosensitivity, but not the photosensitivity due to protoporphyrin. This indicates that Fe may play a role in the uroporphyrin photosensitization in the skin, by accelerating the formation of OH, which may be a major reactive species responsible for the photosensitization in porphyria cutanea tarda.

Animals↗
PubMed2005

Effect of insulin and glucagon on accumulation of uroporphyrin and coproporphyrin from 5-aminolevulinate in hepatocyte cultures.

Primary cultures of chick embryo hepatocytes have been used to study the mechanisms by which various drugs and other chemicals cause accumulation of porphyrin intermediates of the heme pathway. When these cultures are incubated with the heme precursor, 5-aminolevulinic acid (ALA), there is a major accumulation of protoporphyrin. However, in the presence of ALA, addition of insulin caused a striking increase in accumulation of uroporphyrin I and coproporphyrin III, whereas addition of glucagon mainly caused an increase in uroporphyrin I. Treatment with both insulin and glucagon resulted in additive increases in uroporphyrin, but not coproporphyrin. Antioxidants abolished the uroporphyrin I accumulation and increased coproporphyrin III. Insulin caused an increase in uptake of ALA and an increase in porphobilinogen accumulation, suggesting that the accumulation of uroporphyrin I is due to increased flux through the heme pathway. Apparently, this increased flux could particularly affect the utilization of the intermediate hydroxymethylbilane, which would result in accumulation of uroporphyrin I.

Aminolevulinic Acid↗
PubMed1986

Uroporphyrin accumulation produced by halogenated biphenyls in chick-embryo hepatocytes. Reversal of the accumulation by piperonyl butoxide.

Cultures of chick-embryo hepatocytes were used to study the mechanism by which 3,4,3',4'-tetrachlorobiphenyl and 2,4,5,3',4'-pentabromobiphenyl cause accumulation of uroporphyrin. In a previous paper, an isoenzyme of cytochrome P-450 induced by 3-methylcholanthrene had been implicated in this process [Sinclair, Bement, Bonkovsky & Sinclair (1984) Biochem. J. 222, 737-748]. Cells treated with 3,4,3',4'-tetrachlorobiphenyl and 5-aminolaevulinate accumulated uroporphyrin and heptacarboxyporphyrin, whereas similarly treated cells accumulated protoporphyrin immediately after piperonyl butoxide was added. Piperonyl butoxide also restored haem synthesis as detected by incorporation of radioactive 5-aminolaevulinate into haem, and decrease in drug-induced 5-aminolaevulinate synthase activity. The restoration of synthesis of protoporphyrin and haem by piperonyl butoxide was not affected by addition of cycloheximide, indicating recovery was probably not due to protein synthesis de novo. Piperonyl butoxide also reversed uroporphyrin accumulation caused by 3,4,5,3',4',5'-hexachlorobiphenyl, mixtures of other halogenated biphenyls, lindane, parathion, nifedipine and verapamil. The effect of piperonyl butoxide was probably not due to inhibition of metabolism of these compounds, since the hexachlorobiphenyl was scarcely metabolized. Other methylenedioxyphenyl compounds, as well as ellipticine and acetylaminofluorene, also reversed the uroporphyrin accumulation caused by 3,4,3',4'-tetrachlorobiphenyl. SKF-525A (2-dimethylaminoethyl-2,2-diphenyl valerate) did not reverse the uroporphyrin accumulation caused by the halogenated biphenyls, but did reverse that caused by phenobarbital and propylisopropylacetamide. We conclude that the mechanism of the uroporphyrin accumulation cannot be due to covalent binding of activated metabolites of halogenated compounds to uroporphyrinogen decarboxylase.

2-Acetylaminofluorene↗
PubMed1988

Hepatic uroporphyrin accumulation and uroporphyrinogen decarboxylase activity in cultured chick-embryo hepatocytes and in Japanese quail (Coturnix coturnix japonica) and mice treated with polyhalogenated aromatic compounds.

The relationship between hepatic uroporphyrin accumulation and uroporphyrinogen decarboxylase (EC 4.1.1.37) activity was investigated in cultured chick-embryo hepatocytes, Japanese quail (Coturnix coturnix japonica) and mice that had been treated with polyhalogenated aromatic compounds. Chick-embryo hepatocytes treated with 3,3',4,4'-tetrachlorobiphenyl accumulated uroporphyrin in a dose-dependent fashion without a detectable decrease in uroporphyrinogen decarboxylase activity when either pentacarboxyporphyrinogen III or uroporphyrinogen III were used as substrates in the assay. Other compounds, such as hexachlorobenzene, parathion, carbamazepine and nifedipine, which have been shown previously to cause uroporphyrin accumulation in these cells, did not decrease uroporphyrinogen decarboxylase activity. Japanese quail treated with hexachlorobenzene for 7-10 days also accumulated hepatic uroporphyrin without any decrease in uroporphyrinogen decarboxylase activity. In contrast, hepatic uroporphyrin accumulation in male C57BL/6 mice treated with iron and hexachlorobenzene was accompanied by a 20-80% decrease in uroporphyrinogen decarboxylase activity, demonstrating that the assay used for uroporphyrinogen decarboxylase, using pentacarboxyporphyrinogen III as substrate, could detect decreased enzyme activity. Our results with chick hepatocytes and quail, showing uroporphyrin accumulation without a decrease in uroporphyrinogen decarboxylase activity, are consistent with a new two-stage model of the uroporphyria: initially uroporphyrinogen is oxidized by a cytochrome P-450-mediated reaction, followed in rodents by a progressive decrease in uroporphyrinogen decarboxylase activity.

Animals↗
PubMed1976

Multicompartment analysis of 14C-labelled coproporphyrin and uroporphyrin kinetics in human beings.

14C-labelled coproporphyrin I and III and uroporphyrin I were injected intravenously into healthy human subjects. Two experiments were performed with each porphyrin. Counting of blood, urine and faeces was made as a function of time. The coproporphyrin data were simulated by means of an analogy computer by using a four-compartment model with a delay pool. The physiological counterparts to the compartments were considered to be liver, blood and gut. From the blood radioactivity disappearance curve of uroporphyrin three exponential components could be worked out. The least square method was used for the solution of the plasma and urine radioactivity curves. A three-compartment model was constructed to illustrate the kinetics of uroporphyrin I. Coproporphyrin I and III behaved essentially similarly, whilst the kinetic behaviour of uroporphyrin I was completely different from that of coproporphyrins. A rapid hepatic uptake, preferential faecal excretion and a significant enterohepatic circulation were features of coproporphyrin kinetics. Over 70 per cent of the tracer activity of uroporphyrin I was found to accumulate to a rather large pool (volume 16--28 times the plasma volume) from where the back flow to plasma was rather slow. Practically all the uroporphyrin was excreted via urine.

Adult↗
PubMed1991

Iron and uroporphyrin in hepatocytes of inbred mice in experimental porphyria: a biochemical and morphological study.

UNLABELLED: Hexachlorobenzene-induced porphyria is iron dependent and characterized by the decreased activity of uroporphyrinogen decarboxylase and the accumulation of porphyrins in the liver. To examine the relationship between iron and porphyrins in liver tissue, we performed a biochemical and morphological (histological, ultrastructural and morphometrical) study in the livers of C57BL/10 mice. Mice were treated with hexachlorobenzene, iron dextran or the combination of hexachlorobenzene and iron dextran. An accumulation of porphyrins and an increased total iron content were found not only in the livers of mice treated with hexachlorobenzene and iron dextran but also in mice treated with iron dextran alone. In contrast, the amount of porphyrins was only slightly increased in the livers of mice treated with hexachlorobenzene alone. Needle-like structures, representing uroporphyrin crystals, were observed, histologically and ultrastructurally, in hepatocytes of mice treated with hexachlorobenzene and iron dextran and with iron dextran alone. Uroporphyrin crystals and ferritin iron were found in the same hepatocyte. A single uroporphyrin crystal, surrounded by ferritin iron, was observed in a hepatocyte of a mouse treated with hexachlorobenzene alone. Both in the livers of mice treated with hexachlorobenzene and iron dextran and in the livers of mice treated with iron dextran alone, morphometrical analysis showed that an increased area fraction of uroporphyrin crystals was associated with an increased area fraction of ferritin iron in hepatocytes. CONCLUSIONS: In C57BL/10 mice, experimental porphyria can be induced by iron overload alone; uroporphyrin crystals and ferritin iron are located in the same hepatocyte; and the morphological co-occurrence of uroporphyrin crystals and ferritin iron in hepatocytes suggests a role for iron (as ferritin) in the pathogenesis of porphyria.

Animals↗