title: Structure-affinity relationship in the interactions of human organic anion transporter 1 with caffeine, theophylline, theobromine and their metabolites.
abstract: It is well known that human organic anion transporter 1 (hOAT1) transports many kinds of drugs, endogenous compounds, and toxins. However, little is known about the structure-affinity relationship. The aim of this study was to elucidate the structure-affinity relationship using a series of structurally related compounds that interact with hOAT1. Inhibitory effects of xanthine- and uric acid-related compounds on the transport of p-aminohippuric acid were examined using CHO-K1 cells stably expressing hOAT1. The order of potency for the inhibitory effects of xanthine-related compounds on PAH uptake was 1-methyl derivative>7-methyl derivative>3-methyl derivative falling dotsxanthine>1,3,7-trimethyl derivative (caffeine). The order of potency of the inhibition was 1,3,7-trimethyluric acid>1,3-dimethyluric acid>1,7-dimethyluric acid>1-methyluric acid>uric acid. A significant correlation between inhibitory potency and lipophilicity of the tested uric acid-related compounds was observed. The main determinant of the affinity of xanthine-related compounds is the position of the methyl group. On the other hand, lipophilicity is the main determinant of the affinity of uric acid-related compounds.
authors.affiliation: Department of Pharmacy, Hokkaido University Hospital, Kita-14-jo, Nishi-5-chome, Kita-ku, Sapporo, Hokkaido 060-8648, Japan. msuga@med.hokudai.ac.jp
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Sugawara
authors.forename: Takahiro
authors.initials: T
authors.lastname: Mochizuki
authors.forename: Yoh
authors.initials: Y
authors.lastname: Takekuma
authors.forename: Katsumi
authors.initials: K
authors.lastname: Miyazaki
mesh_terms: D000818:Animals; D001692:Biological Transport; D016466:CHO Cells; D002110:Caffeine / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D015394:Molecular Structure; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013805:Theobromine / Q000737:chemistry / Q000494:pharmacology; D013806:Theophylline / Q000737:chemistry / Q000494:pharmacology; D014527:Uric Acid / Q000737:chemistry / Q000494:pharmacology; D014970:Xanthines / Q000737:chemistry* / Q000494:pharmacology*; D010130:p-Aminohippuric Acid / Q000378:metabolism
chemical_list: D027362:Organic Anion Transport Protein 1; D014970:Xanthines; D014527:Uric Acid; D002110:Caffeine; D013806:Theophylline; D013805:Theobromine; D010130:p-Aminohippuric Acid