Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Some patients with acute hereditary porphyrias have seizures and require anticonvulsant therapy, but many anticonvulsants induce exacerbations of the hepatic porphyrias. Recently, several new anticonvulsants have become available. Among these are gabapentin, vigabatrin, felbamate, lamotrigine, and tiagabine. Little is known about their potential for induction of porphyric attacks. We used a cell culture model of primary chicken embryo liver cells, which maintain intact heme synthesis and regulation, to study the effects of these new anticonvulsants on porphyrin accumulation. Treatment of the cells with deferoxamine (250 microM) led to a partial block in heme synthesis, simulating the conditions encountered in human beings with porphyria. Concomitant exposure of these cells to phenobarbital (2 mM) strongly induced accumulation of porphyrins, serving as a positive control in this model. Cells were treated for 20 hours with increasing doses (3.2 to 1,000 microM) of the newer anticonvulsants, with or without deferoxamine. For most of these anticonvulsants 5 to 100 microM is representative of the concentrations achieved in humans with therapeutic doses. Porphyrins were measured spectrofluorometrically as uro-, copro-, and protoporphyrins. Results were confirmed by high-pressure liquid chromatography. Neither vigabatrin nor gabapentin treatment, with or without deferoxamine, led to any increase in porphyrin accumulation. Similar doses of felbamate (with deferoxamine) led to a marked increase in (mainly proto-) porphyrin levels, qualitatively and quantitatively almost identical to the accumulation produced by phenobarbital. Lamotrigine or tiagabine (with deferoxamine) caused similar porphyrin accumulation. Tiagabine treatment up to 100 microM (with deferoxamine) also resulted in very high levels of predominantly proto-porphyrin. In contrast to the other anticonvulsants tested, tiagabine without deferoxamine led to mild porphyrin accumulation. In the presence of deferoxamine, phenobarbital, felbamate, lamotrigine, or tiagabine, but not gabapentin or vigabatrin, increased levels of the mRNA of ALA synthase, the first and rate-controlling enzyme of porphyrin synthesis. Such enzyme induction is a sine qua non for acute porphyric attacks. We conclude that neither vigabatrin nor gabapentin is porphyrogenic, whereas felbamate, lamotrigine, and, especially, tiagabine lead to much accumulation of porphyrins. The latter three anticonvulsants, therefore, may precipitate or exacerbate acute porphyric attacks in humans. We recommend use of vigabatrin or gabapentin, but not felbamate, lamotrigine, or tiagabine, in patients with acute porphyria and seizures.
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PMID:Effects of new anticonvulsant medications on porphyrin synthesis in cultured liver cells: potential implications for patients with acute porphyria. 922 76

Porphyrins and metalloporphyrins are the key pigments of life on earth as we know it, because they include chlorophyll (a magnesium-containing metalloporphyrin) and heme (iron protoporphyrin). In eukaryotes, porphyrins and heme are synthesized by a multistep pathway that involves eight enzymes. The first and rate-controlling step is the formation of delta-aminolevulinic acid (ALA) from glycine plus succinyl CoA, catalyzed by ALA synthase. Intermediate steps occur in the cytoplasm, with formation of the monopyrrole porphobilinogen and the tetrapyrroles hydroxymethylbilane and a series of porphyrinogens, which are serially decarboxylated. Heme is utilized chiefly for the formation of hemoglobin in erythrocytes, myoglobin in muscle cells, cytochromes P-450 and mitochondrial cytochromes, and other hemoproteins in hepatocytes. The rate-controlling step of heme breakdown is catalyzed by heme oxygenase (HMOX), of which there are two isoforms, called HMOX1 and HMOX2. HMOX breaks down heme to form biliverdin, carbon monoxide, and iron. The porphyrias are a group of disorders, mainly inherited, in which there are defects in normal porphyrin and heme synthesis. The cardinal clinical features are cutaneous (due to the skin-damaging effects of excess deposited porphyrins) or neurovisceral attacks of pain, sometimes with weakness, delirium, seizures, and the like (probably due mainly to neurotoxic effects of ALA). The treatment of choice for the acute hepatic porphyrias is intravenous heme therapy, which repletes a critical regulatory heme pool in hepatocytes and leads to downregulation of hepatic ALA synthase, which is a biochemical hallmark of all forms of acute porphyria in relapse.
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PMID:Porphyrin and heme metabolism and the porphyrias. 2372 Feb 91

The porphyrias are a group of rare metabolic disorders, inherited or acquired, along the heme biosynthetic pathway, which could manifest with neurovisceral and/or cutaneous symptoms, depending on the defective enzyme. Neurovisceral porphyrias are characterized by acute attacks, in which excessive heme production is induced following exposure to a trigger. An acute attack usually presents with severe abdominal pain, vomiting, and tachycardia. Other symptoms which could appear include hypertension, hyponatremia, peripheral neuropathy, and mild mental symptoms. In severe attacks there could be severe symptoms including seizures and psychosis. If untreated, the attack might become very severe, affecting the peripheral, central, and autonomic nervous system, leading to paralysis, respiratory failure, hyponatremia, coma, and even death. From the biochemical point of view, acute attacks are involved with increased levels of precursors in the heme biosynthetic pathway, up to the deficient step. Of these precursors, aminolevulinic acid (ALA) is considered to be neurotoxic. Treatment is directed to reduce ALA production by reducing the activity of the enzyme aminolevulinate synthase (ALAS)-most effectively by heme therapy. Cutaneous symptoms are a consequence of elevated porphyrins in the blood stream. These porphyrins react to light; therefore sun-exposed areas are affected, producing fragile erosive skin lesions in porphyria cutanea tarda (PCT) or non-scarring stinging and burning symptoms in erythropoietic protoporphyria (EPP). Unlike the most common neurovisceral porphyria, acute intermittent porphyria (AIP), variegate porphyria (VP), and hereditary coproporphyria (HCP) can have cutaneous symptoms as well. Differentiating them from other cutaneous porphyrias is essential for accurate diagnosis, treatment, and patient recommendations.
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PMID:Porphyria: What Is It and Who Should Be Evaluated? 2955 24