We have isolated a novel liver-specific organic anion transporter, LST-1, that is expressed exclusively in the human, rat, and mouse liver. LST-1 is a new gene family located between the organic anion transporter family and prostaglandin transporter. LST-1 transports taurocholate (K m ‫؍‬ 13.6 M) in a sodium-independent manner. LST-1 also shows broad substrate specificity. It transports conjugated steroids (dehydroepiandrosterone sulfate, estradiol-17␤-glucuronide, and estrone-3-sulfate), eicosanoids (prostaglandin E 2 , thromboxane B 2 , leukotriene C 4 , leukotriene E 4 ), and thyroid hormones (thyroxine, K m ‫؍‬ 3.0 M and triiodothyronine, K m ‫؍‬ 2.7 M), reflecting hepatic multispecificity.LST-1 is probably the most important transporter in human liver for clearance of bile acids and organic anions because hepatic levels of another organic anion transporter, OATP, is very low. This is also the first report of the human molecule that transports thyroid hormones.One of the major function of the liver is the removal of various endogenous and exogenous compounds from the circulation (1, 2). This clearance process involves basolateral membrane transport systems that mediate the hepatocellular uptake of bile acids, organic anions, and organic cations (3, 4). One well studied class of substrates are the bile acids. The uptake of taurocholate is mainly mediated by the Na ϩ /taurocholate cotransporting polypeptide (ntcp) in a Na ϩ -dependent manner (5). The uptake of other bile acids (e.g. cholate) occurs predominantly via a Na ϩ -independent mechanism (2, 4). Some amount of taurocholate is also transported by the Na ϩ -independent mechanism. This Na ϩ -independent carrier system further shows a broad substrate specificity transporting conjugated steroids, cardiac glycosides, and other xenobiotics (4).Initially, the organic anion transporter (oatp) 1 family (oatp1, oatp2, oatp3) was considered to represent the Na ϩ -independent transporting mechanisms in the liver (6 -8). Subsequently, a human cDNA, termed OATP, was isolated (9). However, significant differences were found between human OATP and rat oatp family. First, although the substrate specificities were qualitatively similar, significant differences were found between human OATP-and rat oatp family-mediated initial uptake rates and apparent K m values (10, 11). Second, Northern blot analysis of the human OATP showed considerably high expression in the brain, a pattern that is different from any of the oatp family members. These findings strongly suggest the existence of a different group of organic anion transporters in human liver.Here we report the isolation of a novel human organic anion transporter, termed LST-1, which is expressed exclusively in the liver. When expressed in Xenopus oocytes, many of the functional characteristics of LST-1 were identical to the multispecific transporting mechanisms of human liver. These results suggest that LST-1 is the predominant clearance mechanism of several endogenous and exogenous substrates in human liver. MATERIALS ...

Liver X receptors (LXRK K and LXRL L) are nuclear receptors, which are important regulators of cholesterol and lipid metabolism. LXRs control genes involved in cholesterol e¥ux in macrophages, bile acid synthesis in liver and intestinal cholesterol absorption. LXRs also regulate genes participating in lipogenesis. To determine whether the activation of LXR promotes or inhibits development of atherosclerosis, T-0901317, a synthetic LXR ligand, was administered to low density lipoprotein receptor (LDLR) 3=3 mice. T-0901317 signi¢cantly reduced the atherosclerotic lesions in LDLR 3=3 mice without a¡ecting plasma total cholesterol levels. This anti-atherogenic e¡ect correlated with the plasma concentration of T-0901317, but not with high density lipoprotein cholesterol, which was increased by T-0901317. In addition, we observed that T-0901317 increased expression of ATP binding cassette A1 in the lesions in LDLR 3=3 mice as well as in mouse peritoneal macrophages. T-0901317 also signi¢cantly induced cholesterol e¥ux activity in peritoneal macrophages. These results suggest that LXR ligands may be useful therapeutic agents for the treatment of atherosclerosis.

ABSTRACT:The risk of idiosyncratic drug toxicity (IDT) is of great concern to the pharmaceutical industry. Current hypotheses based on retrospective studies suggest that the occurrence of IDT is related to covalent binding and daily dose. We determined the covalent binding of 42 radiolabeled drugs in three test systems (human liver microsomes and hepatocytes in vitro and rat liver in vivo) to assess the risk of IDT. On the basis of safety profiles given in official documentation, tested drugs were classified into the safety categories of safe, warning, black box warning, and withdrawn. The covalent binding in each of the three test systems did not distinguish the safety categories clearly. However, when the log-normalized covalent binding was plotted against the log-normalized daily dose, the distribution of the plot in the safety categories became clear. An ordinal logistic regression analysis indicated that both covalent binding and daily dose were significantly correlated with safety category and that covalent binding in hepatocytes was the best predictor among the three systems. When two separation lines were drawn on the correlation graph between covalent binding in human hepatocytes and daily dose by a regression analysis to create three zones, 30 of 37 tested drugs were located in zones corresponding to their respective classified safety categories. In conclusion, we established a zone classification system using covalent binding in human hepatocytes and daily dose for the risk assessment of IDTs.

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Many symptoms induced by isolation rearing of rodents may be relevant to neuropsychiatric disorders, including depression. However, identities of transcription factors that regulate gene expression in response to chronic social isolation stress remain elusive. The transcription factor ATF‐7 is structurally related to ATF‐2, which is activated by various stresses, including inflammatory cytokines. Here, we report that Atf‐7‐deficient mice exhibit abnormal behaviours and increased 5‐HT receptor 5B (Htr5b) mRNA levels in the dorsal raphe nuclei. ATF‐7 silences the transcription of Htr5B by directly binding to its 5′‐regulatory region, and mediates histone H3‐K9 trimethylation via interaction with the ESET histone methyltransferase. Isolation‐reared wild‐type (WT) mice exhibit abnormal behaviours that resemble those of Atf‐7‐deficient mice. Upon social isolation stress, ATF‐7 in the dorsal raphe nucleus is phosphorylated via p38 and is released from the Htr5b promoter, leading to the upregulation of Htr5b. Thus, ATF‐7 may have a critical role in gene expression induced by social isolation stress.