The hypothesis that the amino acid used for the conjugation of sulfolithocholate (S-LCA) is a critical determinant of its cholestatic potential was tested in the guinea pig which conjugates 90% of its bile acids with glycine. Twelve groups of animals were used to study the effect of taurine feeding at a concentration of 0.5% in the drinking water for periods of 1, 3, and 5 days before an iv injection of 18 mumol/100 g body weight of S-LCA. Bile flow was monitored in 30-min aliquots over a 3-h period and the bile acid secretion as well as the glycine/taurine ratio of conjugated bile acids were determined. At the end of the various time periods, the livers were examined by light and electron microscopy. Within 3 days after taurine administration there was an increase in bile flow and a reversal of the glycine/taurine ratio with taurine conjugates becoming predominant. Liver morphology was unchanged except for a slight accumulation of lipids after 5 days of taurine feeding. In animals who were not pretreated with taurine, S-LCA injection led to a progressive decrease in bile flow such, that it was reduced to less than 20% at the end of the 3-h collection. S-LCA was conjugated almost exclusively with glycine. In contrast, in the groups fed taurine for 1, 3, and 5 days before the S-LCA injection, bile flow was comparable to that of the groups fed taurine alone. The S-LCA recovered in bile was to a large extent conjugated with taurine. S-LCA animals pretreated with taurine did not exhibit any liver cell changes while the group which had not received taurine before the S-LCA injection showed numerous cytoplasmic vacuoles with normal bile canaliculi. These data show that increasing the availability of taurine through dietary means may exert a protective effect against cholestasis induced by monohydroxy bile acids.