Installing oncofertility programs for common cancers in limited resource settings (Repro-Can-OPEN Study): An extrapolation during the global crisis of Coronavirus (COVID-19) pandemic.

PURPOSE: The state of limited resource settings that Coronavirus (COVID-19) pandemic has created globally should be taken seriously into account especially in healthcare sector. In oncofertility, patients should receive their fertility preservation treatments urgently even in limited resource settings before initiation of anticancer therapy. Therefore, it is very crucial to learn more about oncofertility practice in limited resource settings such as in developing countries that suffer often from shortage of healthcare services provided to young patients with cancer. METHODS: As an extrapolation during the global crisis of COVID-19 pandemic, we surveyed oncofertility centers from 14 developing countries (Egypt, Tunisia, Brazil, Peru, Panama, Mexico, Colombia, Guatemala, Argentina, Chile, Nigeria, South Africa, Saudi Arabia, and India). Survey questionnaire included questions on the availability and degree of utilization of fertility preservation options in case of childhood cancer, breast cancer, and blood cancer. RESULTS: All surveyed centers responded to all questions. Responses and their calculated oncofertility scores showed different domestic standards for oncofertility practice in case of childhood cancer, breast cancer, and blood cancer in the developing countries under limited resource settings. CONCLUSIONS: Medical practice in limited resource settings has become a critical topic especially after the global crisis of COVID-19 pandemic. Understanding the resources necessary to provide oncofertility treatments is important until the current COVID-19 pandemic resolves. Lessons learned will be valuable to future potential worldwide disruptions due to infectious diseases or other global crises.

Increased oxidized low density lipoprotein associated with high ceruloplasmin activity in patients with active acromegaly.

OBJECTIVE: Active acromegaly is associated with increased mortality from cardiovascular causes. Several studies have shown increased atherogenic risk factors and biomarkers of inflammation and atherosclerosis in association with growth hormone excess. The aim of this study was to evaluate oxidized low density lipoprotein (oxLDL) levels and some modulators of LDL oxidative modification in patients with acromegaly. DESIGN: Open transversal study. PATIENTS: Fifteen patients with active acromegaly and 15 controls were studied. MEASUREMENTS: We evaluated the levels of oxLDL, thiobarbituric acid reactive substances (TBARS), ceruloplasmin, bilirubin, uric acid and total reactive antioxidant potential, and the activities of ceruloplasmin, myeloperoxidase, superoxide distmutase, paraoxonase 1, and platelet activating factor acethylhydrolase. Statistical analysis was performed including body mass index as a covariate or as a fixed variable. RESULTS: Patients with acromegaly showed significantly higher levels of oxLDL (120 +/- 19 vs. 86 +/- 20 U/l, P < 0.001) and endothelin (P < 0.05), increased ceruloplasmin activity (P < 0.01) and a trend towards higher values in TBARS concentration (P = 0.07) in comparison to healthy controls. OxLDL was positively associated with GH, IGF-I and its binding protein 3 (r = 0.63, P < 0.001; r = 0.53, P < 0.01; and r = 0.56, P < 0.01; respectively). OxLDL showed direct associations with endothelin-1 (r = 0.53, P < 0.01) and ceruloplasmin activity (r = 0.43, P < 0.05). The other parameters evaluated were similar in both groups. CONCLUSIONS: The increase in plasma oxLDL levels, a direct marker of the plaque formation, could constitute a link between atherosclerosis and active acromegaly. LDL oxidation would not be the consequence of diminished antioxidant defences, but of an enhancement in prooxidant factors like ceruloplasmin.

Hepatic 11 beta-hydroxysteroid dehydrogenase 1 involvement in alterations of glucose metabolism produced by acidotic stress in rat

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11 beta-hydroxysteroid dehydrogenase (HSDs) enzymes regulate the activity of glucocorticoids in target organs. HSD1, one of the two existing isoforms, locates mainly in CNS, liver and adipose tissue. HSD1 is involved in the pathogenesis of diseases such as obesity, insulin resistance, arterial hypertension and the Metabolic Syndrome. The stress produced by HCl overload triggers metabolic acidosis and increases liver HSD1 activity associated with increased phosphoenolpyruvate carboxykinase, a regulatory enzyme of gluconeogenesis that is activated by glucocorticoids, with increased glycaemia and glycogen breakdown. The aim of this study was to analyze whether the metabolic modifications triggered by HCl stress are due to increased liver HSD1 activity. Glycyrrhetinic acid, a potent HDS inhibitor, was administered subcutaneously (20 mg/ml) to stressed and unstressed four months old maleSprague Dawley rats to investigate changes in liver HSD1, phosphoenolpyruvate carboxykinase (PECPK) and glycogen phosphorylase activities and plasma glucose levels. It was observed that all these parameters increased in stressed animals, but that treatment with glycyrrhetinic acid significantly reduced their levels. In conclusion, our results demonstrate the involvement of HSD1 in stress induced carbohydrate disturbances and could contribute to the impact of HSD1 inhibitors on carbohydrate metabolism and its relevance in the study of Metabolic Syndrome Disorder and non insulin-dependent diabetes mellitus (AU)

Hepatic 11 beta-hydroxysteroid dehydrogenase 1 involvement in alterations of glucose metabolism produced by acidotic stress in rat.

11 beta-hydroxysteroid dehydrogenase (HSDs) enzymes regulate the activity of glucocorticoids in target organs. HSD1, one of the two existing isoforms, locates mainly in CNS, liver and adipose tissue. HSD1 is involved in the pathogenesis of diseases such as obesity, insulin resistance, arterial hypertension and the Metabolic Syndrome. The stress produced by HCl overload triggers metabolic acidosis and increases liver HSD1 activity associated with increased phosphoenolpyruvate carboxykinase, a regulatory enzyme of gluconeogenesis that is activated by glucocorticoids, with increased glycaemia and glycogen breakdown. The aim of this study was to analyze whether the metabolic modifications triggered by HCl stress are due to increased liver HSD1 activity. Glycyrrhetinic acid, a potent HDS inhibitor, was administered subcutaneously (20 mg/ml) to stressed and unstressed four months old maleSprague Dawley rats to investigate changes in liver HSD1, phosphoenolpyruvate carboxykinase (PECPK) and glycogen phosphorylase activities and plasma glucose levels. It was observed that all these parameters increased in stressed animals, but that treatment with glycyrrhetinic acid significantly reduced their levels. In conclusion, our results demonstrate the involvement of HSD1 in stress induced carbohydrate disturbances and could contribute to the impact of HSD1 inhibitors on carbohydrate metabolism and its relevance in the study of Metabolic Syndrome Disorder and non insulin-dependent diabetes mellitus.

Differential effects of paraquat on oxidative stress parameters and polyamine levels in two freshwater invertebrates.

Paraquat is still a widely used herbicide in several countries. Its toxic action on plants occurs through a one-electron reduction interfering with the photosynthesis process. By a similar reaction, the herbicide may induce peroxidation processes in non-target animal species. Furthermore, paraquat may interfere with the cellular transport of polyamines. The aim of this work was to investigate some aspects related to paraquat-induction of oxidative stress (lipoperoxidation, enzymatic activities of catalase and superoxide dismutase) and also the levels of polyamines (putrescine, spermidine and spermine) in two species of freshwater invertebrates, the oligochaete Lumbriculus variegatus and the gastropod Biomphalaria glabrata. The results showed that both organisms elicited differential responses. In addition, the data suggested that polyamines may play an important role against lipoperoxidation processes.

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.

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 percent 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 percent 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

Comparison between crab hepatopancreas and rat liver uroporphyrinogen decarboxylase.

We characterized Uroporphyrinogen decarboxylase (UroD) (E.C. 4.1.1.37) in hepatopancreas of the crab Chasmagnathus granulatus as a first step to establish this enzyme as a possible biomarker for environmental contamination. We performed a comparative study of crab UroD with the enzyme UroD present in Wistar rat liver, which is known as a useful indicator of intoxication by polyhalogenated aromatic hydrocarbons (PAHs). The final products were the same in crab and rat UroD: the remaining substrate (8-carboxyl-porphyrinogen), the final product Coproporphyrinogen (4-COOH) and intermediate compounds with 7-, 6- and 5-COOH. The elimination of the second carboxyl group seems to be the rate-limiting step in this multiple decarboxylation, because large amounts of 7-COOH porphyrinogen are accumulated. The V(max)/K(m) ratio was 100-fold higher for rat liver UroD than for crab hepatopancreas UroD, suggesting a higher efficiency of the rat enzyme. Optimum pH for enzyme activity was 7.2 and 6.8 for crab and rat, respectively. Although both systems showed the same optimum temperature (47 degrees C), the activation energy was clearly different, 51.5 kJ/mol for C. granulatus and 5.4 kJ/mol for Rattus norvegicus (Wistar strain). Superdex 75 gel chromatography yielded a single symmetrical peak with an apparent molecular mass of 48+/-3 kDa for crab hepatopancreas UroD, suggesting the existence of only one enzymatic species in C. granulatus.

Phospholipid alterations elicited by hexachlorobenzene in rat brain are strain-dependent and porphyria-independent.

Hexachlorobenzene (HCB) alters phospholipid and heme metabolisms in the liver and Harderian gland. The effects of HCB on phospholipid metabolism, in an organ considered to be non-responsive to its porphyrinogenic effects, remain to be studied. Therefore, as the brain is an organ with this feature, this paper analyzes the effects of HCB on brain phospholipid composition in order to investigate if there is any relationship between HCB-induced porphyrin metabolism disruption and phospholipid alterations. For this purpose, a time-course study of HCB effects on brain phospholipids was performed in two strains of rats differing in their susceptibility to acquire hepatic porphyria: Chbb THOM (low); and Wistar (high). This paper shows for the first time that rat brain phospholipids are affected by HCB exposure. Comparative studies show that HCB-induced disturbances in brain phospholipid patterns are time and strain-dependent. Thus, whereas major phospholipids, phosphatidylcholine and phosphatidylethanolamine were more altered in Wistar rats, minor phospholipids, phosphatidylinositol and phosphatidylserine were more affected in Chbb THOM rats. HCB intoxication led to a sphingomyelin/phosphatidylcholine molar ratio lower than the normal, in both strains. As was expected, brain porphyrin content was not altered by HCB intoxication in either strain. It can be concluded that HCB is able to alter brain phospholipid metabolism in a strain-dependent fashion, and in the absence of alterations in brain heme metabolism. In addition, HCB-induced disturbances in brain phospholipids were not related to the degree of hepatic porphyria achieved by the rats.

How does hexachlorobenzene treatment affect liver uroporphyrinogen decarboxylase?

The aims of the present work were: (1) to investigate whether the strong decrease of liver uroporphyrinogen decarboxylase (UroD) activity observed in experimental porphyria cutanea tarda is due to alteration of the enzymatic protein and (2) to improve the knowledge about the normal liver enzyme. With these purposes, several physicochemical studies for enzymatic characterization were carried out comparatively on the 12-fold purified liver enzyme of both normal and hexachlorobenzene porphyric rat. The study shows that the enzyme from porphyric rats has a higher activation energy, lower reactivity index and lower optimum pH than the normal one. In addition, it did not reach the Vmax at any of the substrate concentrations assayed (up to 28 microM uroporphyrinogen III), while the normal enzyme reached the plateau around 14 microM. The porphyric enzyme appears to be more protected than the normal against the inhibitory action of several metals, particularly Cu2+ and Pb2+, and against thermal inactivation. Zn2+ did not affect enzymatic activity, whereas Cu2+, Hg2+, Fe2+, Pb2+, and Cd2+ lowered the activities of both normal and porphyric enzyme in a dose-related way. It was also observed that the larger the atomic radius in its hydrated state, the lower the effect of the metal. Neither glutathione nor dithiothreitol significantly altered enzymatic activity in the range of concentrations assayed. beta-Mercaptoethanol had diverse effects, as regards both the concentration assayed and the enzymatic sample used. Assays with cystine showed a dual behaviour of both normal and porphyric enzymatic activity. Western blots for both preparations revealed a single band (65 kDa) with a similar intensity. This study show that hexachlorobenzene treatment modifies the physicochemical properties of liver UroD leading to a sharp decrease of its activity, without affecting its antigenic reactivity probably as a consequence of changes at the conformational level promoted by the binding of its reported inhibitor.

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.

Hexachlorobenzene-induced alterations on neutral and acidic sphingomyelinases and serine palmitoyltransferase activities. A time course study in two strains of rats.

Hexachlorobenzene (HCB) induces porphyria both in humans and rodents, and hepatocarcinoma in rodents. In a previous work we observed that HCB produces a continuous decrease in hepatic sphingomyelin (SM) content in Wistar rats. A distinguishing characteristic of sphingolipids breakdown products is their participation in anti-proliferative and apoptotic processes and in the suppression of oncogenesis. As a first step to elucidate the role of SM decrease in the hepatotoxicity induced by HCB, the present study evaluates the metabolic causes of the continuous decrease in hepatic SM content observed in Wistar rats with HCB intoxication, and its relation with porphyria development. For this purpose, the time-course (3, 7, 15, 21 and 28 days) of the effects of HCB on hepatic SM levels and on some of the enzymes of SM synthesis (serine palmitoyltransferase, SPT) and catabolism (sphingomyelinases, SMases) was followed, using two strains of rats differing in their susceptibility to acquire porphyria: Chbb THOM (low) and Wistar (high). HCB (1 g kg(-1) b.w. per day) was administered by gastric intubation as an aqueous suspension. After 5 days of HCB treatment, animals were allowed a 2-day recovery period without HCB administration. Two phases in the HCB-induced damages to sphingolipid metabolism were observed. The first stage (7 days of treatment), common to both strains of rats, was characterized by a decrease in hepatic SM levels (17-25%) and in SPT activity (50-43%), while strain differences were found for the later stage. In Chbb THOM rats, hepatic SM content was restored to normal values concomitantly with an increase in SPT activity (44%, at day 28), and without any increase in SM catabolism. In addition, the level of the other phospholipids was not altered. In Wistar rats, hepatic SM levels decreased continuously throughout the experiment, accompanied by increases in SPT, acidic sphingomyelinase (A-SMase) and neutral sphingomyelinase (N-SMase) activities (86, 28.5 and 78% increase, respectively). A role for glutathione (GSH) in the interstrain differences or a direct effect of HCB on SM metabolism was not found. The present study: (a) demonstrates that N-SMase, A-SMase, and SPT are some of the enzymes that play a role in the HCB-induced decrease of hepatic SM content; (b) finds that HCB-induced alterations of SM metabolism do not correlate with HCB-induced accumulation of hepatic porphyrins; and (c) proposes a link between HCB-induced alterations in phospholipid pattern and in SM metabolism. The increased SM hydrolysis produced as a consequence of SMases induction could be regarded as a cellular response to liver injury elicited by HCB, perhaps acting through the activation of SM signal transduction pathway delaying the proliferative processes observed after long-term treatment with HCB in some rodent species. However, such protective mechanism appears to be strain-dependent.

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.

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.

Effects of hexachlorobenzene on phospholipid and porphyrin metabolism in Harderian glands: a time-course study in two strains of rats.

Hexachlorobenzene, one of the most persistent environmental pollutants, induces uroporphyria and phospholipid alterations in rat liver. Harderian glands produce a secretion that is rich in lipids and accumulate large amounts of protoporphyrin. The aim of the present study was to determine if hexachlorobenzene administration to rats affects phospholipid and porphyrin metabolisms in Harderian glands and if these effects are strain dependent. For this purpose, a time-course study (2, 3 and 4 weeks of hexachlorobenzene treatment) of phospholipid pattern and porphyrin content was performed comparatively in two strains of rats (Wistar and Chbb THOM) which differ in their susceptibility to develop HCB-induced porphyria. Hexachlorobenzene produced decreases in several phospholipid contents, but no changes in phosphatidylcholine levels. While the sphingomyelin/phosphatidylcholine molar ratio remained essentially constant until the third week in Chbb THOM rats, it showed a constant drop in Wistar rats, suggesting a more pronounced alteration of membrane fluidity in the later strain. In regard to porphyrin metabolism, Wistar rats showed an increase in the porphyrin content of the gland, while Chbb THOM animals showed a decrease. The study revealed that not only are the normal parameters of phospholipid and porphyrin metabolism in rat Harderian glands strain dependent, but the response to hexachlorobenzene is also.

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.

[Effect of the thioctamide in relation to the hexachlorobenzene action]. / Efecto de la Tioctamida frente a la acción del Hexaclorobenceno.

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.

Effect of lindane and heptachlor on delta-aminolaevulinate synthase and its regulation.

The effect of lindane and heptachlor on haem metabolism was studied with the aim to elucidate the mechanism of their porphyrinogenic action. The effects of these compounds on delta-aminolaevulinate synthase (ALA-S) and ferrochelatase were evaluated and the mechanism of increase of ALA-S activity was especially studied. The results indicated the following: (1) Lindane and heptachlor produced increases in ALA-S activity; this effect was dependent on the drug dose, the time of treatment, and the development of the animal, the maximum response being obtained prior to hatching. Lindane was observed to have a greater effect on ALA-S than heptachlor. In fact, when effects of lindane and heptachlor were compared we observed that lindane produced: (a) greater increases in ALA-S activity (six fold vs four fold), both with respect to dimethyl sulphoxide (DMSO) controls (3.8+/-0.3 nmol ALA/g liver per h); (b) earlier ALA-S response (1.5 h vs 4 h); (c) responses at lower doses (0.3 mg/egg vs 1 mg/egg). (2) The increase in ALA-S activity produced by lindane or heptachlor is an induction and not an activation process since it depends on protein synthesis and the drugs per se have no effect. Thus, our results obtained from studies in ovo with actinomycin D and cycloheximide suggest that lindane is acting at the translational level while heptachlor interferes at the level of transcription. (3) The study of ALA-S subcellular distribution indicated no accumulation in the cytosol of DMSO controls and in the lindane or heptachlor treated embryos, neither of the chlorinated pesticides alter the normal subcellular distribution of this regulatory enzyme in the liver. (4) Exogenous haem was able to prevent or decrease the induction of ALA-S elicited by both pesticides, thus showing that lindane or heptachlor-induced ALA-S respond to haem regulation. (5) Lindane had no effect on ferrochelatase activity at the doses and times assayed, but heptachlor decreased this enzyme activity. The porphyrinogenic mechanism of lindane and heptachlor is discussed on the basis of the present results.

Efecto de la tioctamina frente a la acción del hexaclorobenceno / Effect of the thioctamide in relation the hexachlorobenzene action

Se estudió el efecto de la intoxicación crónica con hexaclorobenceno en ratas, con y sin administración simultánea de tioctamida. En el grupo que recibió hexaclorobenceno solo, se produjo el esperado desarrollo de porfiria incrementándose la excreción urinaria y el contenido hepático de porfirinas y disminuyendo la actividad Uroporfirinógeno decarboxilasa. El contenido hepático de dienos conjugados no varió, en tanto que el de malondialdehido se incrementó en un grado estadísticamente no significativo. Estos resultados indicarían la existencia de un ligero proceso de peroxidación lipídica. La tioctamida (25 mg/Kg de peso) produjo efectos nocivos antes que protectores, detectados por un aumento de la actividad transaminasa glutámico pirúvica y una inhibición a nivel de la primera etapa de la Uroporfirinógeno decarboxilasa. Los resultados indicarían que: 1) altas dosis de tioctamida producen un decremento en la actividad Uroporfirinógeno decarboxilasa, enmascarando quizás su posible efecto protector frente a la acción del hexaclorobenceno por radicales libres; 2) la Uroporfirinógeno decarboxilasa es un parámetro más sensible que la medición de dienos conjugados o de melondialdehido para ensayar la producción de radicales libres por acción del hexaclorobenceno in vivo. De ser así, la tioctamida, ensayada a dosis menores y no tóxicas, a través de su habilidad como atrapante de radicales libres, quizás pueda proteger contra la acción del hexaclorobenceno. (AU)

Efecto de la tioctamina frente a la acción del hexaclorobenceno / Effect of the thioctamide in relation the hexachlorobenzene action

Se estudió el efecto de la intoxicación crónica con hexaclorobenceno en ratas, con y sin administración simultánea de tioctamida. En el grupo que recibió hexaclorobenceno solo, se produjo el esperado desarrollo de porfiria incrementándose la excreción urinaria y el contenido hepático de porfirinas y disminuyendo la actividad Uroporfirinógeno decarboxilasa. El contenido hepático de dienos conjugados no varió, en tanto que el de malondialdehido se incrementó en un grado estadísticamente no significativo. Estos resultados indicarían la existencia de un ligero proceso de peroxidación lipídica. La tioctamida (25 mg/Kg de peso) produjo efectos nocivos antes que protectores, detectados por un aumento de la actividad transaminasa glutámico pirúvica y una inhibición a nivel de la primera etapa de la Uroporfirinógeno decarboxilasa. Los resultados indicarían que: 1) altas dosis de tioctamida producen un decremento en la actividad Uroporfirinógeno decarboxilasa, enmascarando quizás su posible efecto protector frente a la acción del hexaclorobenceno por radicales libres; 2) la Uroporfirinógeno decarboxilasa es un parámetro más sensible que la medición de dienos conjugados o de melondialdehido para ensayar la producción de radicales libres por acción del hexaclorobenceno in vivo. De ser así, la tioctamida, ensayada a dosis menores y no tóxicas, a través de su habilidad como atrapante de radicales libres, quizás pueda proteger contra la acción del hexaclorobenceno.