Aromatic antiepileptic drugs and mitochondrial toxicity: effects on mitochondria isolated from rat liver.
Idiosyncratic hepatotoxicity is a well-known complication associated with aromatic antiepileptic drugs (AAED), and it has been suggested to occur due to the accumulation of toxic arene oxide metabolites. Although there is clear evidence of the participation of an immune process, a direct toxic effect involving mitochondria dysfunction is also possible. The effects of AAED on mitochondrial function have not been studied yet. Therefore, we investigated, in vitro, the cytotoxic mechanism of carbamazepine (CB), phenytoin (PT) and phenobarbital (PB), unaltered and bioactivated, in the hepatic mitochondrial function. The murine hepatic microsomal system was used to produce the anticonvulsant metabolites. All the bioactivated drugs (CB-B, PB-B, PT-B) affected mitochondrial function causing decrease in state three respiration, RCR, ATP synthesis and membrane potential, increase in state four respiration as well as impairment of Ca2+ uptake/release and inhibition of calcium-induced swelling. As an unaltered drug, only PB, was able to affect mitochondrial respiration (except state four respiration) ATP synthesis and membrane potential; however, Ca2+ uptake/release as well as swelling induction were not affected. The potential to induce mitochondrial dysfunction was PT-B>PB-B>CB-B>PB. Results suggest the involvement of mitochondrial toxicity in the pathogenesis of AAED-induced hepatotoxicity.
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Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-USP, Avenida do Café s/n, 14040-903 Ribeirão Preto, SP, Brazil.
Medina
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Martins
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Mingatto
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Curti
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D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002220:Carbamazepine / Q000378:metabolism / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D010634:Phenobarbital / Q000378:metabolism / Q000633:toxicity*; D010672:Phenytoin / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
D000927:Anticonvulsants; D002220:Carbamazepine; D010672:Phenytoin; D000255:Adenosine Triphosphate; D002118:Calcium; D010634:Phenobarbital