Biomedical subjects

S C Billi

Publications and source records attributed to S C Billi.

9 recordsLinked to original sources

PubMed1987

[Evaluation of deferoxamine capacity to revert a severe porphyria induced by hexachlorobenzene].

The purpose of the present work is to investigate the ability of desferrioxamine (DF) as an iron chelator to revert or decrease a severe experimental porphyria induced by hexachlorobenzene (HCB) in rats; DF treatment started after 17 weeks of HCB intoxication and was continued until the 27th week. The urinary excretions of -aminolevulinic acid (ALA), porphobilinogen and porphyrins were weekly quantitated. At the end of the experiment the animals were sacrificed and hepatic porphyrins, ALA-synthase and porphyrinogen carboxy-lyase activities were determined. The results obtained indicated that, under the present conditions, the administered iron chelator does not improve the disturbance promoted by HCB on the haem pathway. These results were compared with those obtained when the DF was given simultaneously with HCB from the beginning of fungicide administration. In this last situation the chelator was able to delay and diminish the porphyrinogenic effect of HCB.

5-Aminolevulinate Synthetase↗

PubMed1986

Effect of desferrioxamine on the development of hexachlorobenzene-induced porphyria.

The present work deals with the effect of desferrioxamine (DF) on hexachlorobenzene (HCB)-induced porphyria in female rats with the purpose of further investigation of the role of iron in the development of this porphyria. The results obtained show that the repeated injection of DF (three times a week: 100 mg/kg each i.m.) delayed and diminished remarkably the urinary excretion of precursors and porphyrins as well as the accumulation of the latter in liver promoted by HCB (1 g/kg daily given by stomach tube). This was probably due to attenuation by DF of the alterations produced by the fungicide in the two key enzymes: porphyrinogen carboxy-lyase (PCL) and delta-aminolaevulinate synthase (ALA-S). In fact, DF by reducing liver iron levels produced a smaller decrease of the target enzyme (PCL) and a concomitant smaller induction of ALA-S. DF alone did not modify any of these variables or the liver to body weight ratio. DF added at 10(-2) and 10(-3) M to the incubation media of ALA-S and PCL did not alter either of the enzymatic activities, whether in normal or HCB-porphyric preparations. The results obtained show that DF improved the biochemical picture during HCB porphyria. They suggest that iron plays an indirect role in the decrease of PCL enzyme, possibly at the HCB metabolization step. A common iron-involving mechanism for the production of porphyria by different chlorinated compounds is suggested.

5-Aminolevulinate Synthetase↗

PubMed1986

Ability of several hexachlorobenzene metabolites to decrease rat-liver porphyrinogen carboxy-lyase and to produce porphyrin accumulation in chick-embryo liver.

Since hexachlorobenzene (HCB) action seems to be mediated through its metabolites, this study aimed to identify the metabolites and account for the HCB action by evaluating the ability of several of them to inhibit normal rat-liver porphyrinogen carboxy-lyase in vitro and to produce porphyrin accumulation in chick-embryo liver in ovo. Only three of the 11 metabolites assayed produced significant inhibitory effects at 10(-3) M concentration, the order being tetrachlorohydroquinone greater than pentachlorophenol much greater than pentachlorothiophenol. At concentrations below 10(-4) M tetrachlorohydroquinone did not inhibit the enzyme. Most of the metabolites assayed produced porphyrin accumulation, in the following order of strength: chlorophenols greater than chlorothiophenols greater than chlorobenzenes. Phenolic metabolites, therefore, not only produce the greatest amounts of porphyrin accumulation in the liver of the chick embryo but are also the strongest of the metabolite inhibitors of porphyrinogen carboxy-lyase in rat liver. It is possible that they decrease enzymatic activity by binding to the enzyme. This paper discusses the implications of these results for the mechanism of HCB porphyria induction.

Animals↗

PubMed1986

Does feeding of hexachlorobenzene promote structural changes in rat-liver porphyrinogen carboxy-lyase?

This study aimed to determine whether drug treatment produced structural changes in porphyrinogen carboxy-lyase enzymatic protein, leading to altered properties. Rat-liver enzyme was obtained from normal animals and from those with hexachlorobenzene (HCB)-induced porphyria, and several of its properties were comparatively studied. The enzymes from both sources were purified 110-fold. They were similar in subcellular distribution, ammonium sulfate fractionation, calcium phosphate gel adsorption, storage stability, requirements of incubation media, effects of salts and photo-oxidizing agents. The enzymes differed with respect to effect of incubation temperature, pH, aerobiosis, chelating agents, dithiothreitol, methylene blue, heat stability and chromatographic behaviour on DEAE-cellulose and Sephadex G-100. These differences would appear to indicate structural differences between the two types of enzymatic protein. Since the porphyrinogenic action of HCB can be mediated through a metabolite, structural differences could arise through the binding of an inhibitory metabolite to the whole enzyme or through modifications to the protein during its synthesis.

Animals↗

PubMed1986

Rat-liver porphyrinogen carboxy-lyase inhibition as a function of the degree of hexachlorobenzene-induced porphyria.

This study aimed to confirm the presence of an inhibitor in the hexachlorobenzene-porphyric liver that is able to decrease the normal activity of porphyrinogen carboxy-lyase (PCL), to determine whether any relation exists between the degree of hexachlorobenzene-induced porphyria and the ability of a porphyric liver preparation to reduce the enzyme activity of normal liver and to seek extraction methods in order to characterize the inhibitor by gas-liquid chromatography. A perfused liver supernatant (11,000 X g) filtered through a Sephadex G-25 column and heated for 5 min at 100 degrees C was used as the inhibitor source. The results show that the inhibitor was eluted together with a protein peak by gel filtration, the inhibitor was thermostable, the extent of the inhibitory effect reached by this preparation increased with the degree of porphyria, ether and toluene extracts from both heated and non-heated porphyric liver preparations also exhibited an inhibitory effect on the normal activity of PCL and the degree of inhibition depended on the amount of the preparation added. Therefore, there is an inhibitor of PCL activity in the hexachlorobenzene-porphyric liver, the concentration of which increases as the degree of porphyria increases. This inhibitor is soluble in organic solvents and is presently being characterized by gas-liquid chromatography.

Animals↗

PubMed1986

Effect of an iron chelator on the onset of hexachlorobenzene-induced porphyria in rats.

The effect of desferrioxamine on hexachlorobenzene (HCB)-induced porphyria was studied in female rats in order to investigate the role of iron in the development of this porphyria. Repeated injections of desferrioxamine delayed and remarkably diminished the urinary excretion of precursors and porphyrins and the accumulation of porphyrins in the liver. These effects were produced because the desferrioxamine attenuated the alterations produced by HCB in two key enzymes: porphyrinogen carboxy-lyase and delta-aminolaevulinic acid synthase. The effect of desferrioxamine on both enzymes was also studied in vitro. This work showed that iron plays an important role in the onset of HCB-induced porphyria and supplied information on the mechanism of action. A common iron-involving mechanism for the production of porphyria by different chlorinated compounds is suggested.

5-Aminolevulinate Synthetase↗

PubMed1986

Screening for the ability of hexachlorobenzene metabolites to decrease rat liver porphyrinogen carboxy-lyase.

In order to examine inhibitory effects of hexachlorobenzene metabolites on the hepatic porphyrinogen carboxylyase activity, rat liver cytosol was incubated with uroporphyrinogen III and chlorinated phenols, thiophenols, thioanisoles and benzenes. Then, the occurrence of hepta-, hexa-, penta- and tetracarboxyporphyrinogen = coproporphyrinogen (measured as porphyrins) was determined. Inhibitory effects were exerted by tetrachlorohydroquinone, pentachlorophenol, pentachlorothiophenol, 1,2,3,5- and 1,2,4,5-tetrachlorobenzene. Other compounds including hexachlorobenzene which was tested for comparative reasons did not impair uroporphyrinogen decarboxylation. In the presence of tetrachlorohydroquinone, uroporphyrinogen merely was decarboxylated to hepta- and hexacarboxyporphyrinogen. Under the influence of the other 4 compounds with inhibitory effects, pentacarboxyporphyrinogen and coproporphyrinogen were formed additionally. Coproporphyrinogen formation was inhibited completely by tetrachlorohydroquinone, while pentachlorophenol diminished its formation by about 50% and pentachlorothiophenol, 1,2,3,5- and 1,2,4,5-tetrachlorobenzene by less than 10%.

Animals↗

PubMed1985

Ability of several hexachlorobenzene metabolites to induce porphyrin accumulation in chick embryo liver "in ovo".

The present study investigates the ability of several hexachlorobenzene (HCB) metabolites to induce porphyrin accumulation in chick embryo liver cells in ovo, in order to further clarify the role of metabolites in the mechanism of HCB-induced porphyria. HCB per se had no effect on liver porphyrin content, but pretreatment assays with phenobarbital suggested that its metabolic products did. When the direct effect of phenolic, sulfur-containing, and benzenic metabolites of HCB were tested, the following results were obtained. Less chlorinated benzenes (pentachlorobenzene and 1,2,3,4- 1,2,3,5- 1,2,4,5- tetrachlorobenzene) had poor capacity to change the control porphyrin content. On the other hand, the behavior of phenolic metabolites (pentachlorophenol, 2,3,4,5- 2,3,4,6- 2,3,5,6- tetrachlorophenol, 2,3,4- 2,3,5- 2,3,6- 2,4,5- 2,4,6- 3,4,5- trichlorophenol and tetrachlorohydroquinone) as porphyrin inducers was remarkable; the stronger effects were produced by trichlorophenols and tetrachlorohydroquinone. Sulfur containing metabolites produced increases in porphyrin content that were lower than those produced by phenolic compounds and higher than those due to the action of less chlorinated benzenes; only 1-methyl-(2,3,4,5-pentachlorophenyl) sulfoxide was not able to increase porphyrin level. The extent of the effect of the other drugs was pentachlorothiophenol greater than 1-methyl-(2,3,4,5,6-pentachlorophenyl) sulfone greater than tetrachlorothioanisol greater than pentachlorothioanisol. Regarding the mechanism of HCB porphyria, the present results indicate that phenolic metabolites and, in a lower degree, sulfur-containing metabolites, can contribute to the porphyrinogenic ability of HCB.

Animals↗

PubMed1984

[Experimental porphyria induced by chlorinated hydrocarbons. Studies of porphyrinogen carboxy-lyase in the experimental model of human cutaneous delayed porphyria].

The present work tries to elucidate if the strong decrease of porphyrinogen carboxy-lyase (PCL) observed in the experimental porphyria caused by hexachlorobenzene (HCB) is due to the presence of an inhibitor or to a modification of the protein structure of the enzyme. For this purpose: a) cross-assays and heating ones were performed in order to look for the existence of a compound, that present in porphyric animals, would be responsible for the decrease of PCL activity found in them; b) the effect in vitro of HCB, HCB metabolites and other related compounds was studied to find the inhibitor of PCL activity and to look for a relation structure-inhibitory effect; c) hepatic PCL from porphyric and normal rats was purified, and enzyme properties were comparatively studied looking for structural differences between the enzymes obtained from both animal lots. The results indicate that: a) the heat deproteinized porphyric liver preparation produces an inhibition on the normal preparation, but it is smaller than the decrease produced in vivo by the HCB on this enzyme activity, thus other reasons may explain this behavior of PCL in intoxicated animals; b) the HCB had no effect on PCL activity, the phenolic compounds exhibited inhibitions of variable extent that were increased by the presence of electrophilic substituents on the benzenic ring. Pentachlorophenol, the main HCB metabolite, produced inhibition in the in vitro assays, but at doses that were not physiologically significant; thus, it seems not to be the inhibitor found in the heating assays; c) purification of 110 times for the hepatic PCL of both porphyric and normal rats was obtained. Incubation conditions, the effect of salts and chelating agents, the chromatographic behavior in DEAE-cellulose and Sephadex G-100 columns, were comparatively studied with both enzymatic preparations. The effect of sodium diethyldithiocarbamate, sodium pyrophosphate, dithiothreitol, temperature, pH and O2, as well as the chromatographic behavior, would suggest that structural differences in the PCL of porphyric animals may exist; the presence of a thermostable inhibitor could also contribute to the decrease of PCL activity due to HCB.

Animals↗