Mice lacking the nuclear bile acid receptor FXR/BAR developed normally and were outwardly identical to wild-type littermates. FXR/BAR null mice were distinguished from wild-type mice by elevated serum bile acid, cholesterol, and triglycerides, increased hepatic cholesterol and triglycerides, and a proatherogenic serum lipoprotein profile. FXR/BAR null mice also had reduced bile acid pools and reduced fecal bile acid excretion due to decreased expression of the major hepatic canalicular bile acid transport protein. Bile acid repression and induction of cholesterol 7alpha-hydroxylase and the ileal bile acid binding protein, respectively, did not occur in FXR/BAR null mice, establishing the regulatory role of FXR/BAR for the expression of these genes in vivo. These data demonstrate that FXR/BAR is critical for bile acid and lipid homeostasis by virtue of its role as an intracellular bile acid sensor.

Renal microsomal cytochrome P-450 monooxygenasedependent metabolism of arachidonic acid generates a series of regioisomeric epoxyeicosatrienoic acids that can be further metabolized by soluble epoxide hydrolase to the corresponding dihydroxyeicosatrienoic acids. Evidence exists that these metabolites affect renal function and, in particular, blood pressure regulation. To examine this possibility, blood pressure and renal arachidonic acid metabolism were examined in mice with a targeted disruption of the soluble epoxide hydrolase gene. Systolic blood pressure of male soluble epoxide hydrolase-null mice was lower compared with wild-type mice in both the absence and presence of dietary salt loading. Both female soluble epoxide hydrolase-null and wild-type female mice also had significantly lower systolic blood pressure than male wild-type mice. Renal formation of epoxyeicosatrienoic and dihydroxyeicosatrienoic acids was markedly lower for soluble epoxide hydrolase-null versus wild-type mice of both sexes. Although disruption of soluble epoxide hydrolase in female mice had minimal effects on blood pressure, deletion of this gene feminized male mice by lowering systolic blood pressure and altering arachidonic acid metabolism. These data provide the first direct evidence for a role for soluble epoxide hydrolase in blood pressure regulation and identify this enzyme as a novel and attractive target for therapeutic intervention in hypertension. Mammalian soluble epoxide hydrolase (sEH)1 is a cytosolic enzyme expressed in multiple tissues that catalyzes the conversion of a diverse group of epoxides to their corresponding diols (1, 2). The broad spectrum of xenobiotic epoxides metabolized by this enzyme suggests a role in the protection of cells against the potentially harmful effects of these compounds (3). However, sEH hydrates fatty acid epoxides most effectively, with epoxides of arachidonic acid (AA) being among the best substrates (4 -6). This metabolism may result in the formation of metabolites with greater or less biological activity, indicating that sEH may have important physiological functions. Intracellular metabolism of AA by prostaglandin H2 synthase, lipoxygenases, and the cytochrome P-450 (CYP) monooxygenase system generates a number of metabolites, collectively termed eicosanoids, with important biological and cell signaling roles (7-12). CYP-dependent metabolism of AA (Fig. 1) generates three primary classes of metabolites: mid-chain cis-trans-conjugated dienols (5-, 8-, 9-, 11-, 12-and 15-hydroxyeicosatetraenoic acids (HETEs)); -terminal alcohols (16-through 20-hydroxyeicosatetraenoic acids); and, cis-epoxyeicosatrienoic acids (6-, 8,9-, 11,12-, and 14,15 epoxyeicosatrienoic acids (EETs)) (13). EETs have been shown in vitro to be efficiently hydrated to their corresponding dihydroxyeicosatrienoic acids (DHETs) by sEH (5).Evidence exists for a variety of renal functions attributable to EETs and DHETs generated by CYP-dependent epoxygenase activity and sEH, respectively. Most notably, evidence exists for ...

While HLA-B*1502 is unlikely to be associated with carbamazepine-related or aromatic anti-epileptic agent-related SJS/TEN, HLA-B*5801 was significantly associated with allopurinol-related SJS/TEN in Japanese.

Summary Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life‐threatening severe cutaneous adverse reactions. Recently, strong associations of HLA‐B*1502 with carbamazepine‐induced SJS/TEN have been found in Han Chinese patients. These associations have been confirmed in several Asian populations, excluding Japanese. SJS patients carrying HLA‐B*1508, HLA‐B*1511, or HLA‐B*1521, which are members of the HLA‐B75 type along with HLA‐B*1502, were detected in studies in India and Thailand. In the current study, we genotyped the HLA‐B locus from 14 Japanese typical and atypical SJS/TEN patients in whom carbamazepine was considered to be involved in the onset of adverse reactions. Although there were no HLA‐B*1502 carriers, four patients had HLA‐B*1511. Our data suggest that HLA‐B*1511, a member of HLA‐B75, is a risk factor for carbamazepine‐induced SJS/TEN in Japanese.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are severe, cutaneous adverse drug reactions that are rare but life threatening. Genetic biomarkers for allopurinol-related SJS/TEN in Japanese were examined in a genome-wide association study in which Japanese patients (n=14) were compared with ethnically matched healthy controls (n=991). Associations between 890 321 single nucleotide polymorphisms and allopurinol-related SJS/TEN were analyzed by the Fisher's exact test (dominant genotype mode). A total of 21 polymorphisms on chromosome 6 were significantly associated with allopurinol-related SJS/TEN. The strongest association was found at rs2734583 in BAT1, rs3094011 in HCP5 and GA005234 in MICC (P=2.44 × 10(-8); odds ratio=66.8; 95% confidence interval, 19.8-225.0). rs9263726 in PSORS1C1, also significantly associated with allopurinol-related SJS/TEN, is in absolute linkage disequilibrium with human leukocyte antigen-B*5801, which is in strong association with allopurinol-induced SJS/TEN. The ease of typing rs9263726 makes it a useful biomarker for allopurinol-related SJS/TEN in Japanese.