Since its introduction in Europe in 1962, amiodarone has been associated with idiosyncratic hepatotoxicity (Lewis et al., 1989) . A linear correlation between serum AMD concentration and serum ALT activities has been established (Pollak and You, 2003) ; however, in that study, the ALT values did not exceed 3 3 ULN and were not considered to be clinically significant. For the cases of severe liver injury caused by intravenous amiodarone loading, patients' serum ALT activities were up to 10-206 3 ULN. There was usually a 24-72 h delay between the initial loading of AMD and the onset of elevation in ALT activities; and in many cases, the ALT activity returned to normal after a few days of continuation of maintenance dosing (Rätz Bravo et al., 2005) . Accordingly, it is hard to draw a simple linear relationship between the magnitude or frequency of severe hepatotoxicity and serum AMD concentration. An effort to establish a model for AMD-induced liver injury in healthy rodents was unsuccessful. Neither short-term, large dose nor long-term, small dose administration of AMD led to observable liver damage (Young and Mehendale, 1989) . The cause of severe AMD hepatotoxicity is more likely to be a combination of AMD and other factors, e.g., inflammatory Various concentrations of (A) AMD or (B) DEA were added to cultures of Hepa1c1c7 cells together with TNF (3 ng/ml) or saline. Twenty-four hours after treatment, LDH activity released into the culture medium was measured. The percent LDH release was calculated as described in ''Materials and Methods'' section. * indicates significantly different from respective groups not given TNF; # indicates significantly different from respective groups not given AMD or DEA. p < 0.05, n ¼ 3. episodes. In the present study, regardless of cotreatment with LPS, the serum concentration of AMD was about 1100 ng/ml, which is very close to the steady-state serum concentration of AMD in human patients (1500 ng/ml) under long-term oral amiodarone therapy (Pollak et al., 2000) . Our findings support that at this clinically relevant concentration of AMD in serum, hepatotoxicity can be induced by a concurrent inflammatory episode related to LPS exposure.