A cDNA encoding the new member of the multispecific organic anion transporter family, OAT3, was isolated by the reverse transcription-polymerase chain reaction cloning method. Degenerate primers were designed based on the sequences conserved among OAT1, OAT2, and organic cation transporter 1 (OCT1), and reverse transcription-polymerase chain reaction was performed using rat brain poly(A)؉ RNA. The 536-amino acid protein sequence encoded by OAT3 showed 49, 39, and 36% identity to those of OAT1, OAT2, and OCT1, respectively. Northern blot analysis revealed that rat OAT3 mRNA is expressed in the liver, brain, kidney, and eye. When

In the present study, we demonstrate that NLT (novel liver-specific transport protein) is a multispecific organic anion transporter of the liver. The amino acid sequence of NLT shows 42% identity to that of the renal multispecific organic anion transporter, OAT1. When expressed in Xenopus laevis oocytes, NLT mediated uptake of organic anions, such as salicylate, acetylsalicylate, PGE P , dicarboxylates and p-aminohippurate.[ IR C]Salicylate uptake via NLT was saturable (K m = 88.8 þ 23.4 W WM) and sodium-independent. Expression of the mRNA of NLT was detected in the liver and kidney (liverEkidney). We propose that NLT be renamed OAT2.z 1998 Federation of European Biochemical Societies.

In our studies of Na(+)-glucose cotransporter (SGLT) inhibitors as antidiabetic agents, a series of novel 4'-dehydroxyphlorizin derivatives substituted on the B ring was prepared and their effects on urinary glucose excretion were evaluated in rats. Introduction of only a small alkyl group at the 4'-position increased the activity, and 3-(benzo¿bfuran-5-yl)-2',6'-dihydroxy-4'-methylpropiophenone 2'-O-beta-D-glucopyranoside (4) showed the most potent effect. To overcome hydrolysis of compound 4 by beta-glucosidase in the digestive tract, the OH groups on the glucose moiety of compound 4 were modified. Three prodrugs (5, 42, and 55) were more potent than the parent compound 4 by oral administration, and finally 3-(benzo¿bfuran-5-yl)-2',6'-dihydroxy-4'-methylpropiophenone 2'-O-(6-O-methoxycarbonyl-beta-D-glucopyranoside) (5) was selected as a new promising candidate. Compound 5 was metabolized mainly by liver esterase to the active form (4), which was about 10 times more potent than 5 in inhibiting SGLT. In oral glucose tolerance test in db/db mice, compound 5 dose-dependently suppressed the elevation of glucose levels. Single administration of 5 reduced hyperglycemia concurrently with increase of glucose excretion into urine in diabetic KK-A(y) mice. Furthermore, compound 5 suppressed the elevation of blood glucose levels but did not lower it below the normal level even in fasted conditions in KK-A(y) mice. Additionally, long-term treatment with 5 dose-dependently reduced hyperglycemia and HbA1c in KK-A(y) mice. These pharmacological data strongly suggest that compound 5 has a therapeutic potential in the treatment of NIDDM.

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The cycloadducts of CG0 and typical dienes have been isolated by HPLC, and the anthracene and cyclopentadiene adducts characterized by FAB mass and NMR spectroscopy.Studies on fullerenesl have been extensive since the macroscopic synthesis of fullerenes was discovered in 1990.2 It is important to study the chemical reactivity of fullerenes,3.4 in order to gain fundamental knowledge for the development of fullerene derivatives with interesting physical and chemical properties. This paper reports the syntheses, isolation and characterization of several cycloadducts of C a with anthracene, cyclopentadiene, 1,3-diphenylisobenzofuran and 2,3-dimethylbutadiene. Although Diels-Alder reactions of c 6 0 have been reported recently by some groups,S-7 they mentioned that mass spectral characterization of the adducts was hampered by fragmentation into component molecules. Rubin et al. also reported that the reaction products between anthracene and C a could not be isolated and characterized. 6 We have now found that the Diels-Alder adducts of c 6 0 with anthracene or cyclopentadiene can be characterized unequivocally by means of negative ion FAB mass and 1H and 13C NMR spectroscopy.The addition reaction of c 6 0 with anthracene is typical. A mixture of C60 (18 mg), anthracene (5.4 mg) and benzene (5 ml) was refluxed for 12 h under nitrogen. After evaporation under reduced pressure below 50°C, the products were separated by HPLC (LC 908, Japan Analytical Industry, Co., Ltd.) by using gel permeation columns (Jaigel 1H + 1H) and toluene as eluent, to give 5.6 mg (25%) of the mono-adduct Cm(Cl4HI0) and 6.4 mg (24%) of di-adducts C60(C14H10)2.