Toll-like receptor 9 gene mutations and polymorphisms in Japanese ulcerative colitis patients.

AIM: To investigated gene mutations and polymorphisms of TLR9 in Japanese ulcerative colitis (UC) patients. METHODS: Three single nucleotide polymorphisms (SNPs) in TLR9 were identified in healthy controls, and were assessed in 48 UC patients and 47 healthy controls. Control subjects were matched for age, sex and date of blood sampling from among a subgroup of participants. RESULTS: TLR9 -1486CC, 1174GG and 2848AA increase the risk of UC [odds ratio (OR) 2.64, 95% confidence interval (95% CI): 1.73-6.53, P = 0.042], and TLR9 -1486TT, 1174AA and 2848GG decrease the risk of UC (OR 0.30, 95% CI: 0.10-0.94, P = 0.039), although there were no correlations between SNPs and disease phenotype or TLR9 mRNA expression. CONCLUSION: TLR9 polymorphisms are associated with increased susceptibility to UC.

Contribution of OATP (organic anion-transporting polypeptide) family transporters to the hepatic uptake of fexofenadine in humans.

Fexofenadine hydrochloride (FEX), a second generation H(1)-receptor antagonist, is mainly eliminated from the liver into bile in unchanged form. Recent studies have shown that FEX can be accepted by human MDR1 (P-glycoprotein), OATP1A2 [organic anion-transporting polypeptide (OATP)-A, and OATP2B1 (OATP-B)] expression systems. However, other transporters responsible for the hepatic uptake of FEX have not yet been identified. In the present study, we evaluated the contribution of OATP family transporters, namely OATP1B1 (OATP2/OATP-C), OATP1B3 (OATP8), and OATP2B1 (OATP-B), to FEX uptake using transporter-expressing HEK293 (human embryonic kidney) cells. The uptake of FEX in OATP1B3-expressing cells was significantly greater than that in vector-transfected cells. On the other hand, OATP1B1- or OATP2B1-mediated uptake of FEX was not statistically significant. OATP1B3-mediated transport could be explained by a one-saturable component with a Michaelis constant (K(m)) of 108 +/- 11 microM. The inhibitory effect of FEX on the uptake of estrone-3-sulfate (E(1)S), cholecystokinin octapeptide (CCK-8), and 17beta-estradiol-17beta-d-glucuronide (E(2)17betaG) was also examined. Both OATP1B1- and OATP1B3-mediated E(2)17betaG uptake was inhibited by FEX. The K(i) values were 148 +/- 61 and 205 +/- 72 microM for OATP1B1 and OATP1B3, respectively. FEX also inhibited OATP1B3-mediated CCK-8 uptake and OATP1B1-mediated E(1)S uptake with a K(i) value of 83.3 +/- 15.3 and 257 +/- 84 microM, respectively, suggesting that FEX could not be used as a specific inhibitor for OATP1B1 and OATP1B3, although FEX was preferentially accepted by OATP1B3. In conclusion, this is, to our knowledge, the first demonstration that OATP1B3 is thought to be a major transporter involved in hepatic uptake of FEX in humans.