Effects of new anticonvulsant medications on porphyrin synthesis in cultured liver cells

Potential implications for patients with acute porphyria

M. Hahn, O. S. Gildemeister, Gregory Krauss, J. A. Pepe, R. W. Lambrecht, S. Donohue, H. L. Bonkovsky

Research output: Contribution to journalArticle

Abstract

Some patients with acute hereditary porphyrias have seizures and require anticonvulsant therapy, but many anticonvulsants induce exacerbations of the hepatic porphyries. 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 μM) 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 μM) of the newer anticonvulsants, with or without deferoxamine. For most of these anticonvulsants 5 to 100 μM is representative of the concentrations achieved in humans with therapeutic doses. Porphyrins were measured spectrofiuorometrically 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 μM (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.

Original languageEnglish (US)
Pages (from-to)97-106
Number of pages10
JournalNeurology
Volume49
Issue number1
StatePublished - Jul 1997

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Acute Intermittent Porphyria
felbamate
Porphyrins
Deferoxamine
Anticonvulsants
Cultured Cells
Vigabatrin
Liver
Phenobarbital
Heme
Seizures
Therapeutics
Porphyrias
Enzyme Induction
Protoporphyrins
Primary Cell Culture
tiagabine
Chickens
Embryonic Structures
High Pressure Liquid Chromatography

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Hahn, M., Gildemeister, O. S., Krauss, G., Pepe, J. A., Lambrecht, R. W., Donohue, S., & Bonkovsky, H. L. (1997). Effects of new anticonvulsant medications on porphyrin synthesis in cultured liver cells: Potential implications for patients with acute porphyria. Neurology, 49(1), 97-106.

Effects of new anticonvulsant medications on porphyrin synthesis in cultured liver cells : Potential implications for patients with acute porphyria. / Hahn, M.; Gildemeister, O. S.; Krauss, Gregory; Pepe, J. A.; Lambrecht, R. W.; Donohue, S.; Bonkovsky, H. L.

In: Neurology, Vol. 49, No. 1, 07.1997, p. 97-106.

Research output: Contribution to journalArticle

Hahn, M, Gildemeister, OS, Krauss, G, Pepe, JA, Lambrecht, RW, Donohue, S & Bonkovsky, HL 1997, 'Effects of new anticonvulsant medications on porphyrin synthesis in cultured liver cells: Potential implications for patients with acute porphyria', Neurology, vol. 49, no. 1, pp. 97-106.
Hahn, M. ; Gildemeister, O. S. ; Krauss, Gregory ; Pepe, J. A. ; Lambrecht, R. W. ; Donohue, S. ; Bonkovsky, H. L. / Effects of new anticonvulsant medications on porphyrin synthesis in cultured liver cells : Potential implications for patients with acute porphyria. In: Neurology. 1997 ; Vol. 49, No. 1. pp. 97-106.
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