Effects of new anticonvulsant medications on porphyrin synthesis in cultured liver cells: potential implications for patients with acute porphyria.
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.
Hahn
M
M
Department of Medicine, University of Massachusetts Medical Center, Worcester 01655, USA.
Gildemeister
O S
OS
Krauss
G L
GL
Pepe
J A
JA
Lambrecht
R W
RW
Donohue
S
S
Bonkovsky
H L
HL
D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D003676:Deferoxamine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D010634:Phenobarbital / Q000494:pharmacology; D011164:Porphyrias / Q000188:drug therapy; D011166:Porphyrins / Q000096:biosynthesis*
D011166:Porphyrins; D003676:Deferoxamine; D010634:Phenobarbital