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 requi re anticonvulsant therapy, but many anticonvulsants induce exacerbatio ns of the hepatic porphyrias. Recently, several new anticonvulsants ha ve become available. Among these are gabapentin, vigabatrin, felbamate , lamotrigine, and tiagabine. Little is known about their potential fo r induction of porphyric attacks. We used a cell culture model of prim ary chicken embryo Liver cells, which maintain intact heme synthesis a nd regulation, to study the effects of these new anticonvulsants on po rphyrin accumulation. Treatment of the cells with deferoxamine (250 mu M) led to a partial block in heme synthesis, simulating the condition s encountered in human beings with porphyria. Concomitant exposure of these cells to phenobarbital (2 mM) strongly induced accumulation of p orphyrins, serving as a positive control in this model. Cells were tre ated for 20 hours with increasing doses (3.2 to 1,000 mu M) of the new er anticonvulsants, with or without deferoxamine. For most of these an ticonvulsants 5 to 100 mu M is representative of the concentrations ac hieved in humans with therapeutic doses. Porphyrins were measured spec trofluorometrically 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 inc rease in porphyrin accumulation. Similar doses of felbamate (with defe roxamine) led to a marked increase in (mainly proto-) porphyrin levels , qualitatively and quantitatively almost identical to the accumulatio n produced by phenobarbital. Lamotrigine or tiagabine (with deferoxami ne) caused similar porphyrin accumulation. Tiagabine treatment up to 1 00 mu M (with deferoxamine) also resulted in very high levels of predo minantly proto-porphyrin, In contrast to the other anticonvulsants tes ted, tiagabine without deferoxamine led to mild porphyrin accumulation . In the presence of deferoxamine, phenobarbital, felbamate, lamotrigi ne, or tiagabine, but not gabapentin or vigabatrin, increased levels o f 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, ti agabine lead to much accumulation of porphyrins. The latter three anti convulsants, therefore, may precipitate or exacerbate acute porphyric attacks in humans. We recommend use of vigabatrin or gabapentin, but n ot felbamate, lamotrigine, or tiagabine, in patients with acute porphy ria and seizures.