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Enantioselective sulfation of β 2 ‐receptor agonists by the human intestine and the recombinant M‐form phenolsulfotransferase
Author(s) -
Hartman Andrew P.,
Wilson Anne A.,
Wilson Hugh M.,
Aberg Gunnar,
Falany Charles N.,
Walle Thomas
Publication year - 1998
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/(sici)1520-636x(1998)10:9<800::aid-chir4>3.0.co;2-v
Subject(s) - chemistry , enantiomer , stereoselectivity , sulfation , stereochemistry , enantioselective synthesis , agonist , substituent , recombinant dna , receptor , biochemistry , catalysis , gene
The β 2 ‐receptor agonist class of drugs is metabolized in humans almost exclusively by sulfate conjugation. The objective of this investigation was to determine the influence of chemical structure on the stereoselectivity of the sulfoconjugation of these chiral drugs. The pure enantiomers of six β 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 phenolsulfotransferase (PST). Whereas the apparent K m values (K m,app ) for the sulfation of the individual drug enantiomers by the intestinal cytosol varied widely, ranging from 4.8 μM for (S)‐isoproterenol to 889 μM for (S)‐albuterol, these K m,app values were highly correlated with those obtained with M‐PST (correlation coefficient 0.994). In contrast, the M‐PST V max,app values were similar for all drug enantiomers, ranging 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 activity. For isoproterenol, the K m,app for M‐PST was 6.1 times higher for the active (R)‐ than for the inactive (S)‐enantiomer. For other β 2 ‐agonists, the stereoselectivity decreased towards unity as the K m,app increased. However, for albuterol, containing a hydroxymethyl substituent at the aromatic ring, the stereoselectivity was dramatically reversed, with 10 times higher K m,app for the inactive (S)‐ than for the active (R)‐enantiomer. Chirality 10:800–803, 1998. © 1998 Wiley‐Liss, Inc.