The activation of Kupffer cells represents a central mechanism of liver injury involving the production of TNF-alpha. It is known that glycine prevents LPS-induced production of TNF-alpha in isolated Kupffer cells. In this study, the possibility that glycine analogues might affect Kupffer cells was investigated. As a result, aminomethanesulfonic acid (AMS) inhibited the production of TNF-alpha in LPS-stimulated Kupffer cells. Furthermore, LPS treatment caused a transient increase in intracellular calcium ([Ca2+](i)) which was blunted by AMS. Thus, the addition of AMS is protective against the LPS-induced increase [Ca2+](i) and subsequent production of TNF-alpha. Moreover, in vivo studies demonstrated that pretreatment of mice with AMS increased the rate of survival after injection with LPS/D-gal and reduced the TNF-alpha serum level and the mRNA level in the liver. These results indicatethat intake of AMS attenuates the LPS-induced hepatotoxicity resulting from activation of Kupffer cells. (C) 2004 Elsevier Inc. All rights reserved.