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 phenolsulfo transferase (PST) enzyme source and (PAPS)-S-35 as the cosubstrate. Wi th the hepatic cytosol, two distinct sulfation reactions were identifi ed, a high affinity reaction (K(m) 5 to 50 muM) and a low affinity rea ction (K(m) 360 to 2,900 muM). The efficiency of sulfation (V(max)K(m) ) for both reactions was 5-fold higher for (+)- than for (-)-ISO. When the hepatic PSTs were resolved by ion-exchange chromatography, it cou ld be shown that the high affinity reaction was catalyzed by the monoa mine (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 jej unal cytosol with a V(max)/K(m) value 6. 1-fold higher for (+)- than f or (-)-ISO. Finally the platelet, as a potentially useful model tissue , also demonstrated only the high affinity M form reaction with a V(ma x)/K(m) value 5.7-fold higher for (+)- than for (-)-ISO. In summary, t his study has shown that sulfation of ISO by PSTs in various human tis sues is stereoselective and favors the inactive (+)-enantiomer over th e active (-)-enantiomer by about 5-fold, a finding which should be con sidered in the therapeutic use of chiral drugs cleared by sulfate conj ugation. (C) 1993 Wiley-Liss, Inc.