Inhibition of hyaluronan export from human fibroblasts by inhibitors of multidrug resistance transporters.

In a previous report we described the export of hyaluronan from Streptococcus pyogenes by an ABC transporter. Extending these findings a sequence homology search against human proteins revealed a strong homology to the multidrug resistance transporter ABC-B (MDR-1) and ABC-C (MRP 5). Using several inhibitors directed against these and other transporters, a decreased hyaluronan production in cell culture as well as in hyaluronan synthase activity in purified membrane fractions was observed. The inhibitory capacity (IC(50) concentrations) was compared the with reported IC(50)- or the K(i)-concentrations for individual transporters. These analyses revealed that hyaluronan is synthesized within the cytoplasm of mammalian cells and actively secreted into the pericellular space by energy dependent transport proteins. While inhibition of several transport proteins resulted in a decrease of hyaluronan export, inhibition of the MRP5 transporter was the most effective one to decrease hyaluronan in the cell culture supernatant indicating that hyaluronan export is one physiological role of this transport protein.