Abstract
Formation of reactive metabolites like (E)‐2,4‐diene‐VPA is a proposed mechanism for the idiosyncratic hepatotoxicity of valproic acid (VPA). (E)‐2,4‐diene‐VPA is formed by cytochrome P450 (CYP)‐mediated desaturation of (E)‐2‐ene‐VPA or mitochondrial β‐oxidation of 4‐ene‐VPA, which itself is a CYP‐catalyzed metabolite of VPA. (E)‐2,4‐diene‐VPA is reactive and more hepatotoxic than VPA, but direct experimental evidence is needed to evaluate the effect of the in situ generated metabolite on VPA hepatotoxicity. We assessed the effect of modulating the in situ formation of (E)‐2,4‐diene‐VPA by pretreatment with phenobarbital (PB, a CYP inducer) and 1‐aminobenzotriazole (1‐ABT, a CYP inhibitor) on markers of oxidative stress, steatosis and necrosis in sandwich‐cultured rat hepatocytes treated with VPA or (E)‐2‐ene‐VPA. PB increased the metabolism of (E)‐2‐ene‐VPA to (E)‐2,4‐diene‐VPA, and this was accompanied by enhanced toxicity of (E)‐2‐ene‐VPA, whereas 1‐ABT attenuated the increase in the levels of the (E)‐2,4‐diene‐VPA metabolite and toxicity by PB. Neither PB nor 1‐ABT affected (E)‐2,4‐diene‐VPA formation and toxicity in VPA‐treated hepatocytes. In conclusion, in situ formed (E)‐2,4‐diene‐VPA contributes to the toxicity in sandwich‐cultured rat hepatocytes, if generated at sufficiently high levels. [Supported by CIHR and MSFHR]
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