EFFECT OF P450-INDUCERS ON THE HEPATOTOXICITY OF 2-HEXENAL ON THE LEAKAGE OF LACTATE-DEHYDROGENASE FROM PRIMARY CULTURED RAT HEPATOCYTES

We have already reported the effect of several carbonyl compounds such as alkanals, 2-alkenals, glyoxals and malondialdehyde, which are form ed from oxidized lipids, on the leakage of hepatic enzymes from primar y 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-induce rs on the hepatotoxicity of 2-hexenal, since the hepatotoxicity of 0.5 mM 2-hexenal against untreated hepatocytes was reduced to 36.7% and 4 6.3% by the addition of 10 mu M cimetidine and 1 mu M alpha-naphthofla vone, respectively. 3-Methylcholanthrene (MC), phenobarbital (PB), bet a-naphthoflavone (NF) and dexamethasone (DEX) were used as P450-induce rs. In the treatment with 0.5 mM 2-hexenal, the LDH leakage of 3-MC in duced hepatocytes was enhanced to 1.4-fold that of non-induced hepatoc ytes. In the 3-MC induced hepatocytes, the hepatotoxicity of 0.5 mM 2- hexenal was reduced to 38% with alpha-NF (0.1 mu M). Therefore, it is suggested that 2-hexenal is metabolized to hepatotoxic substances by m icrosomal CYP 1A2 species.