S-adenosyl-L-methionine: transcellular transport and uptake by Caco-2 cells and hepatocytes.

S-adenosyl-L-methionine (SAMe) is an endogenous molecule that is known to be protective against hepatotoxic injury. Although oral SAMe appears to be absorbed across the intestinal mucosa, its systemic bioavailability is low. The reason for this is unknown. Using the Caco-2 cell culture model for enterocyte absorption, we determined the mode by which SAMe is transported across this cell monolayer. We also determined the extent it is taken up by both Caco-2 cells and hepatocytes. In Caco-2 cells transport was observed in both apical to basolateral and basolateral to apical directions. The apparent permeability coefficients (P a p p ) appeared to be concentration independent and were similar in both directions (0.7 x 10 - 6 and 0.6 x 10 - 6 cm s - 1 , respectively), i.e. identical to that of the paracellular trans-port marker mannitol (0.9 x 10 - 6 and 0.7 x 10 - 6 cm s - 1 ). This mode of transport was supported by a four-fold increase in the P a p p for SAMe transport in Ca + + -free buffer. Cellular uptake of SAMe was examined in both Caco-2 cells and cultured rat hepatocytes. Uptake by hepatocytes was not saturable in a concentration range of 0.001-100 μM. Accumulation by both cell types was very low, with a cell:medium ratio at equilibrium of only 0.2-0.5. This low cell accumulation supports the finding of paracellular transport as the only mode of cell membrane transport. Increased hepatocellular protection for SAMe may be accomplished by converting SAMe to a more lipid-soluble prodrug.