An in vitro model demonstrating the glucose effect and the influence of fasting on porphyrin metabolism

Schoenfeld, Nili; Greenblat, Yehudit; Epstein, O; Lahav, Meir; Beigel, Yitzhak; Atsmon, A

doi:10.1016/0014-5793(82)80460-2

Cited by 6 publications

(3 citation statements)

References 18 publications

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“…The extreme increase of porphyrin precursor excretion in acute intermittent porphyria, variegate and coproporphyria (13) can only be explained on the basis of the secondarily limiting f riction of uroporphyrinogen synthase (15 -18). Meanwhile the rate limiting function of uroporphyrinogen synthase for the conversion of ALA into protoporphyrin was proven in homogenates (19) and the "glucose effect" was demonstrated in liver cell cultures (11,(20)(21)(22). In the present study 1. the "glucose effect" on porphyrin synthesis is compared in vitro and in vivo and 2. the intriguing role of uroporphyrinogen synthase s a secondary limiting factor is considered in view of the glucose-mediated repression of counterregulation in acute hepatic porphyrias.…”

Section: Introductionsupporting

confidence: 48%

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"Glucose Effect" and Rate Limiting Function of Uroporphyrinogen Synthase on Porphyrin Metabolism in Hepatocyte Culture: Relationship with Human Acute Hepatic Porphyrias

Doss¹,

Sixel-Dietrich²,

Verspohl³

1985

Clinical Chemistry and Laboratory Medicine

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Doss, Sixcl-Dietrich and Verspohl: "Glucose effect" in hepatocyte culture and in acute hepatic porphyrias 505 J. Clin. Chem. Clin. Biochem. Vol. 23, 1985, pp. 505-513 (Received January 26/May 8, 1985) Summary: The effect of glucose on drug-promoted induction of porphyrin synthesis was studied in chick embryo liver cell culture with and without the addition of exogenous -aminolaevulinic acid (ALA). Induction of ALA synthase was abolished by haemin or glucose. Less than 10% 0f porphobilinogen is converted into protoporphyrin. Protoporphyrin synthesis cannot be enhanced by high ALA concentrations. The conversion of exogenous ALA into porphyrins decreases with increasing concentrations of ALA from 0.1 to 2.0 mmol/1, whereas porphobilinogen accumulates, thus reflecting the rate limiting function of Uroporphyrinogen synthase, which is not influenced by glucose. This needle-eye-like function of Uroporphyrinogen synthase within the porphyrin biosynthetic chain explains the urinary increase of ALA and porphobilinogen in the acute phase of variegate and coproporphyria, similar to that in acute intermittent porphyria. i * The "glucose effect" was also investigated in vivo in humans in 32 courses of hereditary acute hepatic . v porphyrias (acute intermittent porphyria, variegate porphyria, coproporphyria and porphobilinogen synthase defect porphyria). Patients were treated with high carbohydrate intake (~500 g/24 h), mainly in the form of glucose infusions. There was a resulting coiisistent and highly significant decrease of porphyrin biosynthesis metabolites, accompanied by clinical improvement in most of the patients. "Glucose-Effeki" und limitierende Funktion der Uroporphyrinogen-Synthase auf den Porphyrinstoffwechsel in der Leberzellkultur in Bezug auf die akuten hepatischen Pörphyrien des MenschenZusammenfassung: Die Wirkung von Glucose auf die Arzneimittel-vermittelte Induktion der Porphyrinsynthese wurde in Hühnerembryo^Leberzellkulturen unter Bedingungen mit endogener und exogener 5-Aminolävulinsäüre (ALS) studiert. Die Induktion der ALS-Synthase konnte durch Hämin oder Glucose aufgehoben werden. Wenjger als 10% Porphobilinogen wird in Porphyrine konvertiert. Die Synthese von Protoporphyrin kann unter hohen ALS-Konzentrationen nicht gesteigert werden. Die Umwandlung exogener ALS in Porphyrine fällt mit steigender Konzentration der ALS von 0,1 bis 2,0 mmol/1, während Porphobilinogen akkumuliert: Hierin spiegelt sich die Umsatz-limitierende Funktion der Uroporphyrinogen-Synthase, die nicht durch Glucose beeinflußt wird". Die Nadelöhr-ähnliche Funktion der Uroporphyrinogen-Synthase innerhalb der Porphyrinbiosynthesekette erklärt den Anstieg von ALS und Porphobilinogen im Urin in der akuten Phase der Porphyria variegata und der Koproporphyrie, welcher demjenigen bei akuter intermittierender Porphyrie ähnlich ist.Der "Glucose-Effekt" in vitro wurde mit dem in vivo beim Menschen verglichen und bei 32 Verläufen hereditärer akuter hepatischer Porphyrieii untersucht (akute intermittierende Porphyrie, Porphyria varie...

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Section: Introductionsupporting

confidence: 48%

“…1). Other investigators also demonstrated that the increase of ALA synthase in vitro by fasting or phenobarbital-mediated induction can be prevented or diminished by glucose (20,22). Fructose, glycerol and lactate mimicked the inhibitory glucose effect on ALA synthase whieh is reversed by 2-deoxyglucose (20).…”

Section: Discussionmentioning

confidence: 97%

"Glucose Effect" and Rate Limiting Function of Uroporphyrinogen Synthase on Porphyrin Metabolism in Hepatocyte Culture: Relationship with Human Acute Hepatic Porphyrias

Doss¹,

Sixel-Dietrich²,

Verspohl³

1985

Clinical Chemistry and Laboratory Medicine

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“…6-Aminolevulinic acid dehydratase was determined in pellets suspended in 125 mM phosphate buffer pH 6.8, according to Schoenfeld et al [14]. 8-Aminolevulinic acid synthase was determined according to Brooker et al [15].…”

Section: Methodsmentioning

confidence: 99%

The heme biosynthetic pathway in the regenerating rat liver

Schoenfeld

Mamet

Epstein

et al. 1987

European Journal of Biochemistry

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Enzymes of heme synthesis, porphyrins and heme content of regenerating rat livers were examined. During the first three days of regeneration the weights of livers of one-third and two-third hepatectomized rats increased 1.5-fold and 2.7-fold and the activity of porphobilinogen deaminase increased 2-fold and 4-fold and was inversely correlated with ferrochelatase activity. 6-Aminolevulinic acid synthase and 6-aminolevulinic acid dehydratase activities were reduced. Concomitantly an increase in the concentration of porphyrins and a decrease in that of heme were observed.The changes in the biosynthetic pathway of heme during rapid growth of the liver are discussed.Previous observations showed that in vitro immortalisation and malignant transformation of cells raise the activity of porphobilinogen deaminase (PBGD) (formerly called uroporphyrinogen synthase) [l, 21. Since both processes increase the rate of growth of cells it was not clear whether the high activity of PBGD was related to rate of growth or to transformation. We, therefore, decided to investigate the effect of rate of growth on PBGD and on other parameters of heme synthesis and metabolism.The partially hepatectomized rat would seem to be a good model for such an investigation. After partial hepatectomy the normally slowly replicating liver cells start dividing rapidly and within 6 days the liver has regained its previous volume [3]. Afterwards no further growth occurs. The mechanisms inducing growth after partial hepatectomy and causing cell division to cease after normal liver size is obtained are unknown. However, they clearly cannot be equated with immortalisation and malignant transformation.Biochemical changes in the regenerating rat and mouse liver have been investigated extensively [4-91. Partial hepatectomy causes a significant decrease in the activities of 6-aminolevulinic acid synthase [4, 91 and of 6-aminolevulinic acid dehydratase (porphobilinogen synthase) [4]. On the other hand, heme oxygenase, the rate-limiting enzyme in heme catabolism, is increased [4,8, 91 and P-450 is decreased [5 -71. These changes return to normal after 3 -7 days.To the best of our knowledge no data concerning the activity of PBGD and ferrochelatase during regeneration of rat liver are known.Correspondence to A. Atsmon, Internal Medicine Department B, Abbreviation. PBGD, porphobilinogen deaminase. Enzymes. Porphobilinogen deaminase (EC 4.3.1.8); &amino-levulinic acid synthase (EC 2.3.1.37); 6-aminolevulinic acid dehydratase or porphobilinogen synthase (EC 4.2.1.24); heme oxygenase (EC 1.14.99.3); ferrochelatase (EC 4.99.1.1); tyrosine aminotransferase (EC 2.6.1.5).Beilinson Medical Center, IL-49 100 Petah Tiqva, Israel MATERIALS AND METHODSThis study was carried out on male Wistar rats, bred at random and weighing 140 -160 g. Animals were subjected either to sham-operation (laparotomy only) or to one-third or two-thirds hepatectomy, under mild ether anesthesia. The two-thirds hepatectomies were carried out in accordance to Higgins and Anderson [3] and in one-third...

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Pk 11195 Aggravates 3,5–Diethoxycarbonyl–1,4–Dihydrocollidine–Induced Hepatic Porphyria in Rats

et al. 1996

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of the heme biosynthetic pathway. Porphyrias are classified There is evidence to suggest that peripheral-type beninto two main categories: hepatic or erythropoietic, dezodiazepine receptors (PBR) are involved in porphyrin pending on whether the excessive porphyrin production is in transport during erythroid differentiation, and it is posthe liver or in the bone marrow, respectively. 3,4 sible that these receptors have an important role in Some chemical agents and drugs can produce biochemical heme biosynthesis. We examined the biochemical and disorders in rats that resemble different forms of human heultrastructural alterations in rat liver following experipatic porphyria. 3,5-Diethoxycarbonyl-1,4-dihydrocollidine mentally induced acute hepatic porphyria, as well as the (DDC) is a fast-acting synthetic compound that is frequently effects of the administration of a selective PBR ligand, used to produce experimental hepatic porphyria in fasting PK 11195. The most severe pathological conditions were rats. 5 The fasting state of the rats is a necessary factor to found in rats that received a combined treatment of the induce the porphyrinogenic effect of DDC, and is termed the porphyrinogenic agent 3,5-diethoxycarbonyl-1,4-dihy-''glucose effect.'' 6 DDC causes the accumulation of a green drocollidine (DDC) and PK 11195. Transmission electron porphyrin-like pigment, N-methylprotoporphyrin IX, which microscopy showed a correlation between the ultrais a potent inhibitor of the enzyme ferrochelatase, which constructural pathology of the liver, the total porphyrin levverts protoporphyrin IX into heme in the heme biosynthetic els in urine and liver, and the porphobilinogen levels in pathway. 7,8 DDC causes greatly increased levels of hepatic urine. Hepatocytes in this acute porphyria showed the protoporphyrin IX and increased levels of urinary excretion of development of large secondary lysosomes containing porphobilinogen (PBG) and d-aminolevulinic acid in a pattern crystalline aggregates of protoporphyrin. Bile canaliculi similar to that of an acute attack of human variegate porwere grossly enlarged, contained aggregates of protophyria. 5 Variegate porphyria is an acute porphyria in which porphyrin crystals, and showed the presence of bile protoporphyrinogen oxidase activity is lowered, and in which thrombi. In addition, prominent bundles of collagen fiprotoporphyrin IX consequently becomes the major circulatbers (fibrosis) were commonly found in livers of rats that ing porphyrin. have been identified in various peripheral tissues as well as in glial brain cells. 10-13 PBR are located mainly in the outer Porphyrins, except for protoporphyrin IX, an intermediate mitochondrial membrane, 14 although they have been found in heme biosynthesis, are by-products that have escaped the in red blood cells, which lack mitochondria. 15 The BZ ligand pathway of heme biosynthesis through irreversible oxidation Ro 5-4864, as well as the isoquinoline carboxamide derivative of the corresponding porphyrinogens.1,2 The porphyrias are PK 111...

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An in vitro model demonstrating the glucose effect and the influence of fasting on porphyrin metabolism

Cited by 6 publications

References 18 publications

"Glucose Effect" and Rate Limiting Function of Uroporphyrinogen Synthase on Porphyrin Metabolism in Hepatocyte Culture: Relationship with Human Acute Hepatic Porphyrias

"Glucose Effect" and Rate Limiting Function of Uroporphyrinogen Synthase on Porphyrin Metabolism in Hepatocyte Culture: Relationship with Human Acute Hepatic Porphyrias

The heme biosynthetic pathway in the regenerating rat liver

Pk 11195 Aggravates 3,5–Diethoxycarbonyl–1,4–Dihydrocollidine–Induced Hepatic Porphyria in Rats

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