Stereoselective sulfate conjugation of isoproterenol in humans: comparison of hepatic, intestinal, and platelet activity.

The stereochemistry of sulfate conjugation of isoproterenol (ISO) was examined with human liver, intestine, and platelets as the phenolsulfotransferase (PST) enzyme source and PAP35S as the cosubstrate. With the hepatic cytosol, two distinct sulfation reactions were identified, a high affinity reaction (Km 5 to 50 microM) and a low affinity reaction (Km 360 to 2,900 microM). The efficiency of sulfation (Vmax/Km) for both reactions was 5-fold higher for (+)- than for (-)-ISO. When the hepatic PSTs were resolved by ion-exchange chromatography, it could be shown that the high affinity reaction was catalyzed by the monoamine (M) form and the low affinity reaction by the phenol (P) form of PST. Only the high affinity (M form) sulfation was detected in the jejunal cytosol with a Vmax/Km value 6.1-fold higher for (+)- than for (-)-ISO. Finally the platelet, as a potentially useful model tissue, also demonstrated only the high affinity M form reaction with a Vmax/Km value 5.7-fold higher for (+)- than for (-)-ISO. In summary, this study has shown that sulfation of ISO by PSTs in various human tissues is stereoselective and favors the inactive (+)-enantiomer over the active (-)-enantiomer by about 5-fold, a finding which should be considered in the therapeutic use of chiral drugs cleared by sulfate conjugation.