Influence of the thr164ile polymorphism in the beta2-adrenoceptor on the effects of beta-adrenoceptor agonists on human lung mast cells.
We have examined the influence of the thr164ile polymorphism in the beta(2)-adrenoceptor on the ability of the beta-adrenoceptor agonists, isoprenaline and salbutamol, to stabilise human lung mast cells. A total of 124 mast cell preparations were genotyped and, of these, 120 were found to be homozygous (thr164thr) at position 164 of the beta(2)-adrenoceptor and 4 were heterozygous (thr164ile). None of the preparations was homozygous for ile at position 164. In these preparations, the effects of isoprenaline and salbutamol on the IgE-mediated release of histamine from mast cells were studied. Both isoprenaline and salbutamol inhibited histamine release in a concentration-dependent manner. Average inhibitory potencies for both agonists, as assessed by pD(2) values, were higher in homozygous than in heterozygous preparations. For isoprenaline, this difference was statistically significant (P < 0.005), whereas for salbutamol, it was not (P = 0.21). These data suggest that the thr164ile polymorphism in the beta(2)-adrenoceptor may influence the extent to which certain beta-adrenoceptor agonists inhibit the responses of mast cells.
Kay
Linda J
LJ
Molecular Pharmacology and Pharmacogenetics, University of Sheffield, The Royal Hallamshire Hospital (Floor L), Glossop Road, Sheffield S10 2JF, UK.
Chong
Lee K
LK
Rostami-Hodjegan
Amin
A
Peachell
Peter T
PT
D000322:Adrenergic Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000494:pharmacology; D006579:Heterozygote; D006632:Histamine / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D007532:Isoleucine / Q000235:genetics*; D007545:Isoproterenol / Q000494:pharmacology; D008168:Lung / Q000166:cytology*; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011943:Receptors, Adrenergic, beta / Q000235:genetics*; D013912:Threonine / Q000235:genetics*
D000322:Adrenergic Agonists; D011943:Receptors, Adrenergic, beta; D007532:Isoleucine; D013912:Threonine; D006632:Histamine; D007545:Isoproterenol; D000420:Albuterol