Effect of P450-Inducers on the Hepatotoxicity of 2-Hexenal on the Leakage of Lactate Dehydrogenase from Primary Cultured Rat Hepatocytes

Abstract

We have already reported the effect of several carbonyl compounds such as alkanals, 2-alkenals, glyoxals and malondialdehyde, which are formed from oxidized lipids, on the leakage of hepatic enzymes from primary cultured rat hepatocytes. In the case of 2-alkenals, the leakage of lactate dehydrogenase (LDH) took place in a dose-dependent manner and the hepatotoxicity was inhibited by the addition of ascorbic acid and glutathione. In this paper, we investigated the effects of P450-inducers on the hepatotoxicity of 2-hexenal, since the hepatotoxicity of 0.5 mM 2-hexenal against untreated hepatocytes was reduced to 36.7% and 46.3% by the addition of 10μM cimetidine and 1μM α-naphthoflavone, respectively. 3-Methylcholanthrene (MC), phenobarbital (PB), β-naphthoflavone (NF) and dexamethasone (DEX) were used as P450-inducers. In the treatment with 0.5 mM 2-hexenal, the LDH leakage of 3-MC induced hepatocytes was enhanced to 1.4-fold that of non-induced hepatocytes. In the 3-MC induced hepatocytes, the hepatotoxicity of 0.5 mM 2-hexenal was reduced to 38% with α-NF (0.1 μM). Therefore, it is suggested that 2-hexenal is metabolized to hepatotoxic substances by microsomal CYP 1A2 species.