ENANTIOSELECTIVE SULFATION OF BETA(2)-RECEPTOR AGONISTS BY THE HUMAN INTESTINE AND THE RECOMBINANT M-FORM PHENOLSULFOTRANSFERASE

The beta(2)-receptor agonist class of drugs is metabolized in humans a lmost exclusively by sulfate conjugation. The objective of this invest igation was to determine the influence of chemical structure on the st ereoselectivity of the sulfoconjugation of these chiral drugs. The pur e enantiomers of six beta(2)-agonists, including those clinically most widely used, were all effectively sulfated both by the cytosol of the human intestine and the recombinant human M-form phenolsulfotransfera se (PST). Whereas the apparent K-m values (K-m,K-app) for the sulfatio n of the individual drug enantiomers by the intestinal cytosol varied widely, ranging from 4.8 mu M for (S)-isoproterenol to 889 mu M for (S )-albuterol, these K-m,K-app values were highly correlated with those obtained with M-PST (correlation coefficient 0.994). In contrast, the M-PST V-max,V-app values were similar for all drug enantiomers, rangin g from 276 to 914 pmol min(-1) mg(-1) protein, implying that substrate binding to M-PST by far is the main determinant of the sulfation acti vity. For isoproterenol, the K-m,K-app for M-PST was 6.1 times higher for the active (R)- than for the inactive (S)-enantiomer. For other be ta(2)-agonists, the stereoselectivity decreased towards unity as the K -m,K-app increased. However, for albuterol, containing a hydroxymethyl substituent at the aromatic ring, the stereoselectivity was dramatica lly reversed, with 10 times higher K-m,K-app for the inactive (S)- tha n for the active (R)-enantiomer. (C) 1998 Wiley-Liss, Inc.