Biomedical subjects

C Aldonatti

Publications and source records attributed to C Aldonatti.

12 recordsLinked to original sources

PubMed2002

The decrease in uroporphyrinogen decarboxylase activity induced by ethanol predisposes rats to the development of porphyria and accelerates xenobiotic-triggered porphyria, regardless of hepatic damage.

We evaluated the porphyrinogenic ability of ethanol (20% in drinking water) per se, its effect on the development of sporadic porphyria cutanea tarda induced by hexachlorobenzene in female Wistar rats (170-190 g, N = 8/group), and the relationship with hepatic damage. Twenty-five percent of the animals receiving ethanol increased up to 14-, 25-, and 4.5-fold the urinary excretion of delta-aminolevulinate, porphobilinogen, and porphyrins, respectively. Ethanol exacerbated the precursor excretions elicited by hexachlorobenzene. Hepatic porphyrin levels increased by hexachlorobenzene treatment, while this parameter only increased (up to 90-fold) in some of the animals that received ethanol alone. Ethanol reduced the activities of uroporphyrinogen decarboxylase, delta-aminolevulinate dehydrase and ferrochelatase. In the ethanol group, many of the animals showed a 30% decrease in uroporphyrinogen activity; in the ethanol + hexachlorobenzene group, this decrease occurred before the one caused by hexachlorobenzene alone. Ethanol exacerbated the effects of hexachlorobenzene, among others, on the rate-limiting enzyme delta-aminolevulinate synthetase. The plasma activities of enzymes that are markers of hepatic damage were similar in all drug-treated groups. These results indicate that 1) ethanol exacerbates the biochemical manifestation of sporadic hexachlorobenzene-induced porphyria cutanea tarda; 2) ethanol per se affects several enzymatic and excretion parameters of the heme metabolic pathway; 3) since not all the animals were affected to the same extent, ethanol seems to be a porphyrinogenic agent only when there is a predisposition, and 4) hepatic damage showed no correlation with the development of porphyria cutanea tarda.

Animals↗

PubMed2000

Heme metabolism after discontinued hexachlorobenzene administration in rats: possible irreversible changes and biomarker for hexachlorobenzene persistence.

The aim of the present study was to determine whether short-term administration of hexachlorobenzene (HCB) (1 g/kg body wt., suspended in water, 5 days/week), could cause and maintain marked porphyria in the absence of the exogenous drug, and whether porphyria parameters can be useful as biomarkers of HCB persistence in rats. Hepatic uroporphyrinogen decarboxylase activity, its inhibitor formation, porphyrin content and composition were studied in Wistar rats treated with the fungicide for 1, 2, 3, or 4 weeks and then withdrawn for a 20-week period. The time course of urinary porphyrin excretion was studied for 7 weeks either by continuous treatment for the entire period, or a 1-week HCB administration. The degree of porphyria achieved by rats after 20 weeks of suspended HCB administration was severe, independent of the length of the treatment, and even higher than that observed in animals analysed immediately at the end of each treatment. Rats treated with HCB for 1 week showed a modest decrease in uroporphyrinogen decarboxylase and low inhibitor formation, and exhibited a greater enzyme inhibition, inhibitor formation, hepatic porphyrin accumulation, and an altered pattern of porphyrin composition in the absence of the exogenous drug. Independent of the treatment, urinary porphyrins rose after a delay of 5 weeks. Substantial amounts of HCB were still found in fat of rats treated with HCB for 1 week, after a withdrawal period of 20 weeks. These results suggest that the high persistence of HCB in tissues acts as a continuous source of the xenobiotic, and stimulus for heme biosynthesis derangement. The alterations induced by HCB within 1 week of treatment could be regarded as an initial trigger for irreversible damage on heme metabolism. Thus, abnormalities in heme biosynthesis can be considered effective markers of HCB persistence in rats or of irreversible HCB-induced damage. Taking into account the delayed and enhanced metabolic effects of HCB, it is advisable that porphyria parameters should be evaluated not only immediately after exposure, but also some time afterwards, especially in susceptible and occupationally-exposed populations.

Adipose Tissue↗

PubMed2000

Heme metabolism and lipid peroxidation in rat kidney hexachlorobenzene-induced porphyria: A compartmentalized study of biochemical pathogenic mechanisms.

In the present study, the effects of hexachlorobenzene (HCB) on lipid peroxidation and heme metabolism in the different constitutive suborgans of the kidney were determined. For this purpose, conjugated diene and malondialdehyde levels, as lipid peroxidation parameters, and porphyrin accumulation, uroporphyrinogen decarboxylase activity, and its inhibitor formation, as measures of heme metabolism, were determined in renal cortex, medulla, and papilla. Adult Wistar rats were treated with HCB during 1, 2, 3, or 4 weeks. A significant increase in cortical conjugated dienes was observed from the 1st week of treatment. The malondialdehyde levels rose by 47, 34, and 28% after 2, 3, and 4 weeks of intoxication, respectively. The porphyrin content showed a tenfold increase after 4 weeks of treatment, and the uroporphyrinogen decarboxylase activity was reduced by 26 and 58% with respect to control values after 3 and 4 weeks of treatment, respectively. The results demonstrate a direct correlation between the oxidative environment and the effect elicited by the drug on heme metabolism in the renal cortex. In contrast, in papilla and medulla, where the antioxidant systems were higher, HCB showed no porphyrinogenic effect.

Animals↗

PubMed1999

Effect of alpha lipoic acid amide on hexachlorobenzene porphyria.

The aim of this work is to study the effect of thioctamide--the commercial form of alpha lipoic acid amide--on the porphyrinogenic action of hexachlorobenzene (HCB). For this purpose, porphyria was induced in rats by chronic HCB treatment, with or without simultaneous thioctamide administration. Two different groups of rats were used as reference: one treated with vehicle (control) and the other treated with thioctamide (TO). Urine delta aminolevulic acid, porphobilinogen, and porphyrin excretions were lower in the HCB + TO treated group than in the HCB group, and the same happened with liver uroporphyrin accumulation. On the other hand, the second stage of uroporphyrinogen-decarboxylase activity was significantly higher in the HCB + TO group than in the HCB group. delta aminolevulic acid synthase activity was higher in the HCB group. Hepatic thiobarbituric acid reactive substances were lower in HCB + TO group than in HCB group. Thus, we might suggest that TO would decrease HCB effects by means of its free radical scavenging ability, and by having a direct effect on uroporphyrinogen-decarboxylase activity.

Animals↗

PubMed1999

Porphyria-induced hepatic porphyrinogen carboxy-lyase inhibitor and its interaction with the active site(s) of the enzyme.

Porphyrinogen carboxy-lyase is an enzyme that sequentially decarboxylates uroporphyrinogen III (8-COOH) to yield coproporphyrinogen III (4-COOH). In mammals this enzyme activity is impaired by hexachlorobenzene treatment, through generation of an enzyme inhibitor. The interaction of porphyrinogen carboxy-lyase inhibitor, extracted from the liver of hexachlorobenzene-treated rats, with substrate decarboxylation sites on the enzyme, was studied using four different carboxylated substrates belonging to the isomeric III series of naturally-formed porphyrinogens containing 8-,7-,6- and 5-COOH. Similar inhibitor effects were elicited against all the substrates assayed, with the exception of pentacarboxyporphyrinogen III in which decarboxylation was not inhibited to same extent. Enzyme protection assays in the presence of the different substrates, indicated that each porphyrinogen protects its own decarboxylation from inhibitor action. Preincubation of the inhibitor with normal enzyme increased its inhibitory effect. On the other hand, preincubation of both enzyme and inhibitor with superoxide dismutase or mannitol, did not alter inhibitory activity. Preincubation of the inhibitor with a number of amino acids showed that only arginine and its derivative N alpha-Benzoyl-L-Arginine ethyl ester interact with the inhibitor, noticeably reducing its ability to inhibit porphyrinogen carboxy-lyase. Albumin, histidine, serine, cysteine and imidazol, were unable to quench inhibitor activity. The present results indicate that the inhibitor acts at the binding site of each porphyrinogen. Taking into account that arginine is related to enzyme activity, and that histidine is found at the binding site of the substrates, the results suggest that the inhibitor could bind to arginine residues, blocking the access of substrates to histidine and altering the adequate orientation for decarboxylation by masking the positively charged active site necessary for porphyrinogen binding to the enzyme. In addition an indirect effect of the inhibitor mediated through free radicals could be discarded.

Animals↗

PubMed1998

[Effect of the thioctamide in relation to the hexachlorobenzene action].

Chronic administration of Hexachlorobenzene, with or without the simultaneous administration of Tioctamide was assayed. Hexachlorobenzene alone produced the characteristic porphyria, detected through an increase of the urinary excretion and the hepatic accumulation of porphyrins, as well as by a decrease of the Uroporphyrinogen decarboxylase activity. The content of hepatic conjugated dienes did not change while those of malondialdehyde increased, although without reaching levels of statistical significance. These results would indicate the occurrence of an light lipid peroxidation process. The Thioctamide (25 mg/kg body weight) produced more noxious effects than protective ones, which were detected by a high level of Glutamate piruvate transaminase activity and a decrease of the hepatic Uroporphyrinogen decarboxylase activity, at its first step of decarboxylation. These results might indicate that: 1) high doses of Thioctamide decreases Uroporphyrinogen decarboxylase activity, masking its possible protective effect from Hexachlorobenzene's action through free radicals production and, 2) Uroporphyrinogen decarboxylase is a more sensitive parameter than conjugated dienes or malondialdehyde levels to assay the free radicals in vivo Hexachlorobenzene production. In any case, the Thioctamide assayed in lower and non toxic doses, perhaps might protect against Hexachlorobenzene's action through its free radical scavenger ability.

5-Aminolevulinate Synthetase↗

PubMed1997

Time course of hexachlorobenzene-induced alterations of lipid metabolism and their relation to porphyria.

A great deal of information concerning the effects of hexachlorobenzene on the haem metabolic pathway has been obtained but little is known about the effects of the drug on lipid metabolism. Consequently, the time course of phospholipid metabolism alteration caused by this xenobiotic was evaluated as related to changes in porphyrin metabolism with the aim to understand better the interregulation of both metabolisms. Female Wistar rats were treated with HCB (1 g/kg) over a 1-8 week period. Individual phospholipid content, [32P] incorporation, total lipid content, lipid peroxidation, uroporphyrinogen decarboxylase activity, its inhibitor generation and porphyrin content, were the parameters measured in the liver of treated rats. Phospholipid metabolism-with the exception of sphingomyelin-presents a biphasic behaviour, in both the endogenous contents and de novo synthesis. The turning point between both phases is the time at which levels of porphyrin and conjugated dienes increase, the latter compounds being involved in oxidative processes. On the other hand, sphingomyelin decreases continuously during the 8 weeks of treatment. It was also found that the malondialdehyde content increased during the early stages. The time sequence for haem metabolism parameters showed that the accumulation of porphyrins occurs after the decrease in uroporphyrinogen decarboxylase activity and the enzyme inhibitor formation, which are early events (first and second weeks). Porphyrins could not by themselves exacerbate uroporphyrinogen decarboxylase impairment or inhibitor generation. This study shows that hexachlorobenzene alters simultaneously phospholipid and porphyrin metabolisms from the early stages, and generates an oxidative environment that favours porphyrinogens and lipid oxidation at later stages. So, this oxidative environment links the alterations on both metabolisms.

Animals↗

PubMed1991

Sex comparison of heme pathway in rats bearing hepatic tumors.

The present study was undertaken to explore the effect of the presence of hepatic tumors induced by diethylinitrosamine (DENA) on the metabolic heme pathway, and to assess whether these tumors can modify the response of rats to the porphyrinogenic drug hexachlorobenzene (HCB) and whether the above mentioned effects occur to a greater extent in females than males. The results obtained showed that: a) Females were more susceptible to the hepatocarcinogenicity of DENA than males. b) Female normal and DENA treated rats were more susceptible than male rats to the porphyrinogenicity of HCB. c) The presence of hepatic DENA induced tumors could diminish basal hepatic ferrochelatase activity. d) Hepatic tumors could modify the response of animals to a porphyrinogenic drug such as HCB. Thus, both female and male DENA/HBC rats accumulated more porphyrins and showed a lower delta-aminolevulinate synthase and uroporphyrinogen I synthase induction than HCB rats. e) The heme pathway was functional in DENA induced tumors in both male and female rats but they were little affected by HCB.

5-Aminolevulinate Synthetase↗

PubMed1991

Influence of hepatic tumors caused by diethylnitrosamine on hexachlorobenzene-induced porphyria in rats.

The response of female BDVI rats bearing diethylnitrosamine(DENA)-induced hepatic tumors to the porphyrinogenic action of hexachlorobenzene (HCB) was studied. (1) The heme pathway operates in these tumors but they were less affected by HCB than the liver. (2) Tumors did not accumulate porphyrins although the surrounding liver accumulated more porphyrins than livers treated with HCB. (3) DENA/HCB livers which developed a well defined tumor showed slightly less porphyrinogen carboxylyase inhibition and delta-aminolaevulinate synthase induction than HCB rats. (4) The results of the present work suggest that endogenously formed porphyrins would be unable to be accumulated by DENA-induced tumors when the tumoral development precedes the onset of the porphyria.

5-Aminolevulinate Synthetase↗

PubMed1990

Synergistic effect of mammary tumors on hexachlorobenzene-induced porphyria in rats.

The response of animals bearing N-nitroso-N-methylurea (NMU)-induced mammary tumors to the porphyrinogenic action of hexachlorobenzene (HCB) was studied. delta-Aminolevulinic acid (ALA), porphobilinogen and porphyrins in urine, ALA-synthase and porphyrinogen carboxylase activities and porphyrin content in liver and tumor were measured. The results obtained indicate that the metabolic heme pathway operates in mammary tumors but tumor response to HCB treatment could not be detected. HCB administration produced an earlier and greater hepatic porphyria in tumor-bearing rats than in healthy rats suggesting that the presence of tumors exacerbates the action of HCB.

5-Aminolevulinate Synthetase↗

PubMed1986

[Evaluation of porphyrinogenic effect of lindane in rats].

In order to study the porphyrinogenic ability of lindane in mammals, rats were treated with the pesticide suspended with the aid of Tween or dissolved in oil during about 3 months. The urinary excretion of porphyrins and its precursors: delta-aminolaevulinate (ALA) and porphobilinogen (PBG), as well as the faecal excretion of coproporphyrin (COPRO) and protoporphyrin (PROTO) was determined weekly. At the end of the treatment the hepatic activities of ALA Synthase (ALA-S), the first and rate limiting enzyme of haem pathway, and porphyrinogen carboxy-lyase (PCL), enzyme which sequentially decarboxylates uroporphyrinogen (8 COOH) to coproporphyrinogen (4 COOH), were assayed. Lindane moderately increased the urinary excretion of porphyrins and its precursors, being the former the mainly affected parameter. The faecal excretion of COPRO and PROTO was also increased. However, the hepatic activity of ALA-S was not altered. This would suggest that the regulatory haem pool was not affected. Nor was PCL activity altered in spite of being the key enzyme for the attack of other chlorinated compounds. Although hexachlorobenzene (HCB), a very well known porphyrinogenic drug, and lindane are chemically related and generate similar metabolites, the last one produces a small and qualitatively different alteration of haem biosynthesis. This may be related with the absence or scarce formation of the reactive metabolite that accounts for the porphyrinogenic ability of HCB.

5-Aminolevulinate Synthetase↗

PubMedDate not supplied

Evaluation of the porphyrinogenic risk of antineoplastics.

The use of antineoplastics is common in cancer therapy, and some of them have been associated with the development of porphyria in patients with cancer. However, knowledge of their effects on the haeme metabolic pathway is at present scarce and unclear. So, the present study evaluates the porphyrinogenic ability of nine antineoplastics (both alkylating and non-alkylating). These were tested either alone or in conjunction with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (latent porphyria model) in chick embryos and in mice. The results obtained suggest that the use of cyclophosphamide, azathioprine, 5-fluorouracil, busulphan, procarbazine and hexamethylmelamine be avoided in the treatment of porphyric patients. On the other hand, dacarbazine, chlorambucil and melphalan are non-porphyrinogenic. We also provide evidence showing that neither the presence of the mustard group in the structure of the antineoplastic nor alterations in ferrochelatase or protoporphyrinogen oxidase activities are responsible for the porphyrinogenic ability of cyclophosphamide.

Alkylating Agents↗