Alcohol-Induced Decrease in Uroporphyrinogen Decarboxylase Activity in Rat Liver and Spleen
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Chronic alcohol consumption in rats leads to a decrease in uroporphyrinogen decarboxylase activity in liver and spleen, associated with a pathologic porphyrinuria. These findings show the toxic effect of alcohol in the biochemical pathogenesis of chronic hepatic porphyria. The results confirm experimentally the transition of symptomatic coproporphyrinuria to chronic hepatic porphyria as observed in man, and the progression of biochemical phases of chronic hepatic porphyria into the clinical phase, i.e., the development from latent to manifest stages under chronic alcohol ingestion.Keywords:
Uroporphyrinogen III decarboxylase
Pathogenesis
Chronic hepatic
Alcohol is a agenrphyrinogenic agent which may cause disturbances in porphyrin metabolism in healthy persons as well as biochemical and clinical manifestations of acute and chronic hepatic porphyrias. After excessive alcohol infestion in man a secondary hepatic coproporphyrinuria develops transiently, which persists in alcoholic liver disease. The alcohol-liver-porphyrinuria syndrome ranges first among the secondary hepatic disturbances of porphyrin metabolism. In acute hepatic porphyrias (acute intermittent porphyria, porphyria varigata and hereditary coproporphyria) alcohol induces delta-aminolevulinic acid synthase because in these porphyrias the control mechanisms of porphyrinogen and heme synthesis in liver are disturbed ("molecular regulatory diseases"). On the contrary, in chronic hepatic porphyrias, which are already associated with liver damage ("membrane diseases"), alcohol potentiates the disturbance of the decarboxylation of uro- and heptacarboxyporphyrinogen, which is followed by a hepatic accumulation of uro- and heptacarboxyporphyrin and their sometimes extreme urinary excretion. Alcohol may transform a symptomatic coproporphyrinuria into chronic hepatic porphyria. One can deduct from experimental and clinical studies that in liver alcohol inhibits the enzymes coproporphyrinogen oxidase, delta-aminolevulinic acid dehydratase and uroporphyrinogen decarboxylase and induces delta-aminolevulinic acid synthase. Abstinence from alcohol is an important measure in the therapy and prophylaxis of all hepatic porphyrias.
Uroporphyrinogen III decarboxylase
Porphyria cutanea tarda
Porphobilinogen
Chronic hepatic
Ethanol metabolism
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Uroporphyrinogen III decarboxylase
Hexachlorobenzene
Chronic hepatic
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Porphyria cutanea tarda (PCT) is the most frequent type of porphyria. As a rule, it is associated with chronic liver disease. The disturbance of the hepatic porphyrin metabolism is regarded as the cause and center of the disease. Thus PCT is also designated as chronic hepatic porphyria. Reduced activity of hepatic uroporphyrinogen decarboxylase is considered the most important prerequisite for the development of PCT. The cutaneous manifestations are preceded by non-cutaneous latent phases of various degrees. These phases may be proved by urinary porphyrin studies, especially by the increase of uro- and heptacarboxyporphyrins. The hereditary form of PCT can be identified by the determination of the uroporphyrinogen decarboxylase in erythrocytes. The enzyme deficiency in red blood cells follows dominant autosomal inheritance. Alcohol and estrogens are the predominant factors of clinical manifestation. The application of chloroquine in low doses has proved an effective treatment. The present review includes a report on the workshop "Cutaneous Porphyrias", which reflects the clinical, toxic, pharmacogenetic, pathophysiological, enzymologic, and molecular aspects from the authors' point of view.
Porphyria cutanea tarda
Uroporphyrinogen III decarboxylase
Chronic hepatic
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Chronic hepatic
Subclinical infection
Hepatic dysfunction
Liver enzyme
Uroporphyrinogen III decarboxylase
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Porphyria cutanea tarda
Uroporphyrinogen III decarboxylase
Chronic hepatic
Chronic liver disease
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Uroporphyrinogen III decarboxylase
Porphyria cutanea tarda
Chronic hepatic
Subclinical infection
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Uroporphyrinogen III decarboxylase
Hexachlorobenzene
Decarboxylation
Chronic hepatic
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Citations (33)
Erythrocyte delta-aminolaevulinic acid dehydratase (ALAD) activity was estimated in chronic hepatic porphyria, correlated with some tests of liver function and compared with enzyme activity in chronic liver diseases. 24 patients with chronic hepatic porphyria, 22--with chronic liver diseases and 30--controls were examined. European standardised method for the determination of ALAD activity blood was used. The significantly lowest activity was found in porphyric patients even after reactivation with zinc and dithiothreitol. There was no significant difference between ALAD activity in chronic liver diseases and controls. These results and lack of correlation between enzyme activity and liver function tests suggest that ALAD activity is decreased in chronic hepatic porphyria and is independent of liver damage.
Porphyria cutanea tarda
Chronic hepatic
Uroporphyrinogen III decarboxylase
Porphobilinogen synthase
Liver function
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Alcohol is a porphyrinogenic agent which may cause disturbances in porphyrin metabolism in healthy persons as well as biochemical and clinical manifestations of acute and chronic hepatic porphyrias. After excessive consumption of alcohol, a temporary, clinically asymptomatic secondary hepatic coproporphyrinuria is observable, which can become persistent in cases of alcohol-induced liver damage. Nowadays, the alcohol-liver-porphyrinuria syndrome is the first to be mentioned in secondary hepatic disturbances of porphyrin metabolism. Acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria and hereditary coproporphyria) are considered to be molecular regulatory diseases, in contrast to non-acute, chronic hepatic porphyria, clinically appearing as porphyria cutanea tarda (PCT). Porphyrins do not accumulate in the liver in acute porphyrias, whereas in chronic hepatic porphyrias they do. Thus, chronic hepatic porphyria is a porphyrin-accumulation disease, whereas acute hepatic porphyrias are haem-pathway-dysregulation diseases, characterized in general by induction of delta-aminolevulinic acid synthase in the liver and excessive stimulation of the pathway without storage of porphyrins in the liver. The clinical expression of acute hepatic porphyrias can be triggered by alcohol, because alcohol augments the inducibility of delta-aminolevulinic acid synthase. In chronic hepatic porphyrias, however, which are already associated with liver damage, alcohol potentiates the disturbance of the decarboxylation of uro- and heptacarboxyporphyrinogen, which is followed by a hepatic accumulation of uro- and heptacarboxyporphyrin and their sometimes extreme urinary excretion. Especially in persons with a genetic deficiency of uroporphyrinogen decarboxylase, but also in patients with the so-called sporadic variety of PCT, alcohol is able to transform an asymptomatic coproporphyrinuria into PCT. Alcohol has many biochemical and clinical effects on porphyrin and haem synthesis both in humans and laboratory animals. Ethanol suppresses the activity of porphobilinogen synthase (synonym: delta-aminolevulinic acid dehydratase), uroporphyrinogen decarboxylase, coproporphyrinogen oxidase and ferrochelatase, whereas it induces the first and rate-limiting enzyme in the pathway, delta-aminolevulinic acid synthase and also porphobilinogen deaminase. Therefore, teetotalism is a therapeutically and prophylactically important measure in all types of hepatic porphyrias.
Porphyria cutanea tarda
Uroporphyrinogen III decarboxylase
Chronic hepatic
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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.
Uroporphyrinogen III decarboxylase
Hexachlorobenzene
Porphyria cutanea tarda
Chronic hepatic
Liver enzyme
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