Porphyria In Rats Research Articles

Melatonin Formation in Pineal Gland from Rats with Hexachlorobenzene Experimental Porphyria

Hexachlorobenzene produces an experimental hepatic porphyria in rats, which is similar to human porphyria cutanea tarda, with hyperpigmentation as one of its characteristic features. Alterations in tryptophan metabolism have been previously observed in this chronic porphyria. Melatonin formation from tryptophan via serotonin shows diurnal rhythmicity in the pineal gland, and higher values are observed during the dark phase of an imposed light-dark cycle. The purpose of this study was to determine the contents of tryptophan and its metabolites in pineal gland of normal and hexachlorobenzene-treated rats in order to find alterations potentially related to porphyria cutanea tarda. Results show that in animals with this experimental porphyria some tryptophan metabolite levels (serotonin and 5-hydroxyindoleacetic acid) increase only during the light period, whereas tryptophan content remained equal to the controls. Hydroxyindole-O-methyltransferase activity also increases by light in pineal gland from hexachlorobenzene-treated rats. On the other hand, tryptophan is converted to melatonin in the dark period, but this route is not exacerbated in hexachlorobenzene porphyria. The relevance of these alterations is discussed in relation to hyperpigmentation, neoplastic and oxidative stress processes associated with this porphyria.

What's your diagnosis? Respiratory distress in rats.

What's your diagnosis? Respiratory distress in rats.

Estrogen and antioxidants in hexachlorobenzene-induced hepatic porphyria in rats

Estrogen and antioxidants in hexachlorobenzene-induced hepatic porphyria in rats

Water quality criteria assessment for chlorinated benzenes using the quantitative structure activity relation approach and porphyrogenic endpoint in rats

Sub‐chronic toxicity data on rats for various chlorobenzenes have been utilized to show a high correlation between log dose porphyria and log P, the log of the octanol:water partition coefficient. Various predictive equations were calculated as a function of log P (log P)2 log P + (log P)2 log 1/SW and (log 1/Sw)2. All have good correlations except for the case of (log 1/Sw)2. The calculated log criterion values obtained from predicted dose for porphyria in rats were regressed against log P and the log of the bioconcentration factor (log B) and various single and multi‐parameter regression equations were found. Criteria predicted from log P values and sub‐chronic toxicity data tended to be between 10–100 times larger than criteria calculated by other means (chronic toxicity, carcinogenicity or organoleptic). This quantitative structure activity relation approach has the advantage of providing criteria for all congeners in a series, whether or not they have been tested for carcinogenicity.

Development of an experimental model for the study of hexachlorobenzene-induced hepatic porphyria in the rat

Hexachlorobenzene (HCB) induces hepatic porphyria in rats. Various protocols of repeated cumulative and daily doses of HCB administered for several weeks until porphyria develops have been traditionally used. In order to undertake studies on early biochemical events occurring in HCB-induced porphyria, we have designed an experimental model involving the administration of a minimal amount of HCB inducing a fully developed porphyria in a well defined and predictable time frame. Groups of Sprague-Dawley rats were given (po, in 10 ml/kg of corn oil) a cumulative dose of 1500 mg HCB/kg as 50 mg/kg for 6 weeks (5 days/week) or 100 mg/kg for 3 weeks (5 days/week). In female, but not male, rats treated for 6 weeks, HCB caused a porphyria as measured by urinary uroporphyrin and hepatic porphyrin levels; this total dose given to female rats in 3 weeks was not, however, porphyrinogenic. Female rats were given 12 consecutive daily doses of 50 mg HCB/kg followed by a no-treatment period of 30 days; this cumulative dose of 600 mg HCB/kg induced a porphyria after 6 weeks. The approximate minimally effective cumulative dose inducing porphyria was determined to be 400 mg HCB/kg, regardless of the magnitude of the daily dose (25, 50, or 100 mg/kg). Finally, the administration of a cumulative dose of 500 mg HCB/kg (50 mg/kg, 5 days/week for 2 weeks or 100 mg/kg/day for 5 days) induced after 5 to 6 weeks a porphyria that persisted for more than 500 to 600 days. These results suggest that induction of porphyria is dependent upon the administration of a threshold cumulative dose of HCB during an initial phase followed by a delay period with no further treatment during which full development of biochemical alterations in the heme synthesis cycle occurs.

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 δ-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.

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. δ-Aminolevulinic acid (ALA), porphobilinogen and porphyrins in urine, ALA-synthase and porphyrinogen carboxylyase 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.

Development of hexachlorobenzene porphyria in rats: Time sequence and relationship with lipid peroxidation

The relationship between the development of porphyria and free-radical formation induced by hexachlorobenzene was studied in iron-overloaded rats. The first sign of porphyria, an increase in porphyrins in the liver, was detected at day 22. Liver malondialdehyde was also increased at day 22. During the following weeks, liver porphyrins and malondialdehyde increased simultaneously, accompanied by a decrease in uroporphyrinogen decarboxylase activity and glucose-6-phosphate activity in liver, and a high excretion of porphyrins in the urine. In the rats given hexachlorobenzene, changes were detected in the pattern of lipids in the liver microsomes. In comparison with the controls, there were decreases in C20:4 and C22:5 fatty acids, whereas the fatty acid C20:3w6 was increased. In this study of hexachlorobenzene-induced liver damage there was no difference in the time course of the development of porphyria and that of lipid peroxidation.

Studies on the etiology of trace metal-induced porphyria: Effects of porphyrinogenic metals on coproporphyrinogen oxidase in rat liver and kidney

Studies were conducted on the etiology of trace metal-induced porphyria in rats, with particular emphasis on the action of metals on hepatic and renal coproporphyrinogen oxidase. Prolonged exposure of rats to methyl mercury hydroxide or sodium arsenate at subtoxic dose levels in drinking water resulted in a progressive coproporphyrinuria, reaching highest rates of coproporphyin excretion 5 weeks after initiation of exposure. The development of coproporphyrinuria was accompanied by substantial metal accumulation in the kidney and a significant decrease in renal, but not hepatic, coproporphyrinogen oxidase activity. During prolonged exposure to either metal, the rates of coproporphyrin excretion and metal accumulation by the kidney continued to increase for 2 to 3 weeks following maximal inhibition of renal coproporphyrinogen oxidase. Acute treatment studies and studies in vitro support the conclusion that the kidney is the principal source of excess urinary coproporphyrin during metal exposure. These observations demonstrate that metal-induced coproporphyrinuria is predominantly of renal etiology and that impairment of renal coproporphyrinogen oxidase is a principal cause of this effect.

Development of hexachlorobenzene porphyria in rats: Relationship to lipid peroxidation

Development of hexachlorobenzene porphyria in rats: Relationship to lipid peroxidation

Mechanism of hexachlorobenzene-induced porphyria in rats. Effect of phenobarbitone pretreatment.

The effect of a pretreatment with phenobarbitone (PB) on the porphyrinogenic action exerted by hexachlorobenzene (HCB) was examined in female rats. Kinetic studies of enzyme function after HCB poisoning showed that porphyrinogen carboxy-lyase was the only enzyme of haem biosynthesis that markedly lowered its activity. Both stages of uroporphyrinogen (UPG) III decarboxylation were decreased. This enzyme, together with UPG I synthase (increased levels) were the first enzymes altered. Subsequently, an increase in delta-aminolaevulinate (AmLev) synthase and ferrochelatase was detected; AmLev dehydratase was the last to increase. On long-term exposure, PB alone did not modify the basal values of haem intermediates; only the content of cytochrome P-450 increased. All the enzyme activities studied showed no significant changes, except ferrochelatase, which increased. With both drugs the metabolic impairment promoted by HCB was accelerated and enhanced by prior PB treatment leading to the onset of an earlier and stronger porphyria. A more noticeable accumulation and excretion of higher carboxylated porphyrins and precursors was more promptly observed as a consequence of the early porphyrinogen carboxy-lyase blockade and the concomitant induction of AmLev synthase. Although the enzymic activities of both AmLev dehydratase and ferrochelatase were enhanced, this response differed in time. For UPG I synthase this pretreatment elicited lower values than those found in the HCB group. Cytochrome P-450 contents were immediately and slightly enhanced by all the drugs, but the values for the combined treatment were the lowest. Of the several hypotheses that could explain the action of HCB on the haem pathway, our results would suggest that the porphyrinogenic action of HCB is mediated by some of its metabolic products.

Iron absorption during the development of hexachlorobenzene-induced porphyria in rats.

The absorption of iron [59Fe-(FeSO4)] from jejunal loops was studied in rats after acute and subacute exposure to hexachlorobenzene (HCB). Female rats were given orally 100 mg HCB/kg body weight or fed a diet with 0, 500, 1,000, or 2,000 parts/10(6) HCB for 1 and 4 weeks. Male rats were fed on diets with 0 and 2,000 parts/10(6) HCB only. An increase in total urinary porphyrins and a decrease in the ratio of coproporphyrin to uroporphyrin in individual 24-h urine samples indicated different stages of porphyria in the rats at the time of determination of iron absorption. After acute oral administration of HCB, iron absorption decreased to about 70% of control values. After feeding the animals on HCB-containing diets, relative liver weight as well as total plasma protein increased depending on time and dose. The absorption of iron was not altered after 1 week of HCB exposure. After 4 weeks, the uptake of iron into the carcass decreased to less than 40% of control values, independently of dose and sex. The uptake of iron into the liver, expressed as percentage of the amount absorbed by the intestine, decreased significantly after 1 and 4 weeks of HCB feeding. No correlation could be observed between iron metabolism and urinary porphyrin excretion. The development of HCB-induced porphyria in rats is apparently not accelerated by an increased iron absorption.

Uroporphyrinogen decarboxylase deficiency in experimental chronic hepatic porphyria.

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.

Cutaneous cytochrome P-450 activity during hexachlorobenzene-induced experimental porphyria in rats.

Cutaneous cytochrome P-450 activity during hexachlorobenzene-induced experimental porphyria in rats.

The nature of hepatic cytochrone P-450 induced in hexachlorobenzene-fed rats.

1. The effect of feeding with a diet containing 0.2% (w/w) hexachlorobenzene on hepatic and urinary porphyrins and hepatic cytochrome P-450 was studied at various time intervals in female Wistar rats. 2. Hexachlorobenzene administration for 45 days resulted in the development of porphyria in rats, which biochemically closely resembles symptomatic porphyria in humans, with elevation of urinary uroporphyrin excretion, hepatic uroporphyrin content, and hepatic cytochrome P-450 content, in addition to appearance of porphyrins of the isocoproporphyrin (P1) series in the faeces. 3. Spectral studies of the induced hepatic cytochrone P-450 at 45 days with carbon monoxide and ethyl isocyanide as ligands indicated the presence of a greater admixture of a haemoprotein distinct from cytochrome P-450. 4. Study in vitro of the kinetics of two reactions, namely aminopyrine N-demethylation and 3,4-benzpyrene hydroxylation, catalysed by the hepatic microsomal cytochrom P-450-dependent enzyme system, suggested that hexachlorobenzene induced a form of cytochrome P-450-dependent enzyme system, suggested that hexachlorobenzene induced a form of cytochrome P-450 with different catalytic properties from those of forms induced by either phenobarbital or 3-methylcholanthrene.

Study of the effects of certain drugs on experimental porphyria in rats.

The effect of ethanol, phenobarbitone, griseofulvin or chloroquine on 3,4-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced porphyria in rats has been studied in experiments lasting up to 40 days. Ethanol, phenobarbitone or griseofulvin given later, in addition to DDC, resulted in a clearly greater porphyrin excretion and liver porphyrin concentration than with DDC alone. Chloroquine at first increased, then decreased porphyrin excretion and liver porphyrin was lowered. No drug without DDC was porphyrogenic.

Porphyrin Metabolism in Renal Diseases

Fluorescence microscopy in experimental hexachlorobenzene porphyria in rats has demonstrated porphyrin deposits in the epithelial cells of the proximal renal tubules and the loop of Henle. In the glom

Experimental porphyria induced by 3-[2-(2,4,6-trimethylphenyl)-thioethyl]-4-methylsydnone

Administration of 3-[2-(2,4,6-trimethylphenyl)-thioethyl]-4-methylsydnone (TTMS) induces hepatic porphyria in rats, mice and dogs. The protoporphyrin pigment in livers of rats and mice is found mainly in bile ducts and leads to bile duct proliferation and portal inflammation. Dog livers contain protoporphyrin predominantly in bile canaliculi. The birefringence of the pigment appears to be associated with bilamellar components within the pigment. The markedly depressed catalase activity in livers of rats does not increase after clofibrate administration. The catalase activity of mouse liver is depressed slightly and responds to clofibrate treatment.

Hexachlorobenzene-induced porphyria in rats—Relationship between porphyrin excretion and induction of drug metabolizing liver enzymes

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.

Experimental hepatic porphyria induced by polychlorinated biphenyls

Aroclor 1254, which consists of a mixture of polychlorinated biphenyls (PCBs) containing 54% chlorine, produced an experimental hepatic porphyria in rats resembling hexachlorobenzene poisoning and human porphyria cutanea tarda. The PCB-induced porphyria is characterized by delayed development, increased excretion of urinary uroporphyrins, accumulation of 8- and 7-carboxyporphyrins in the liver and increased drug-metabolizing capacity of the liver. Cytochrome P-450 and microsomal heme were increased maximally at 1 week, in the absence of an increase in the rate-limiting enzyme in heme synthesis, δ-aminolevulinic acid (ALA) synthetase. Induction of ALA synthetase and porphyria occurred later, after 2–7 months' exposure to PCBs. No induction of ALA synthetase could be demonstrated prior to the onset of porphyria. Marked induction of ALA synthetase occurred 5 hr after large single doses of Aroclor 1254; however, the doses required were larger than those used to produce porphyria when administered chronically, and induction appeared to be related to the marked increase in cytochrome P-450 seen 24 hr after administration of the drug.