Genetic susceptibility to hepatoxicity due to bosentan treatment in pulmonary hypertension.

BACKGROUND: Hepatotoxicity is a major side effect of treatment with bosentan in patients with pulmonary hypertension (PH). Bosentan is metabolized by the cytochrome CYP2C9 and inhibits the bile salt export pump, which is encoded by ABCB11. This suggests that genetic variants of CYP2C9 and/or ABCB11 may predispose patients to bosentan-induced liver injury. MATERIAL AND METHODS: PH patients with (n = 23) or without (n = 25) an increase of alanine aminotransferase (ALT) or aspartate-aminotransferase (AST) during bosentan therapy were included in our analysis. Functionally relevant alleles of CYP2C9 and 16 representative variants of ABCB11 were genotyped. Data were analyzed using logistic regression. RESULTS: Variants of ABCB11 were not associated with bosentan-induced liver injury. In contrast, variant alleles of CYP2C9 were more common in patients with elevated transaminases (allele frequency 52%) compared to controls (allele frequency 24%, P = 0.04, odds ratio 3.5, 95% confidence interval 1.01-11.8). CONCLUSION: Our data indicate hepatotoxicity of bosentan from decreased hepatic metabolism due to common variants of CYP2C9.

[Optimizing antidepressant pharmacotherapy in a case of inflammatory bowel disease and major depression]. / Antidepressive Therapieoptimierung in einem Fall von chronisch-entzündlicher Darmerkrankung bei unipolarer Depression.

OBJECTIVE: In the framework of a case report on a patient suffering from major depression and inflammatory bowel disease we address the pharmacotherapeutical options in case of subtherapeutic mirtazapine levels. METHODS: We applied therapeutic drug monitoring (TDM) and cytochrome P450 2D6 genotyping, and switched to an orodispersible tablet. RESULTS AND CONCLUSION: Thus, mirtazapine plasma levels could be raised and clinical improvement of the depressive symptoms was achieved.

Activation of Notch signaling in human colon adenocarcinoma.

Notch and Wnt signaling function together to regulate colonic progenitor cell division and differentiation. Studies in mice have also shown that Notch signaling is required for adenoma formation in response to elevated Wnt-pathway signaling that occurs in the APCMin mouse model of human adenomatous polyposis coli. We therefore used in situ hybridization to analyze expression of Notch ligands, receptors and fringe genes, as well as the Notch target gene, HES1, in human colorectal cancer (CRC). In a small cohort of tumors, JAGGED ligands, NOTCH1, LFNG and HES1 were expressed at levels similar to, or higher than, levels observed in the crypt. To explore the possibility that Notch signaling may play a quantitative role in human CRC we next analyzed HES1 mRNA expression in 130 tumors, each associated with outcome data. The vast majority of these tumors expressed HES1, although at varying levels. Absolute expression levels did not correlate with patient survival. These results establish that JAG ligands and NOTCH1, as well as Notch receptor activation are consistent features of human CRC and support the notion that many of these tumors, like the APCMin mouse, may respond to anti-Notch therapeutic regimes.

Effect of macrophage overexpression of murine liver X receptor-alpha (LXR-alpha) on atherosclerosis in LDL-receptor deficient mice.

UNLABELLED: Background- The nuclear liver X receptor-alpha (LXR-alpha) has been implicated in the regulation of intracellular cholesterol homeostasis, inflammatory response, and atherosclerosis susceptibility. The aim of the present study was to test whether transgenic expression of LXR-alpha might affect these mechanisms and result in a reduction of atherosclerosis. METHODS AND RESULTS: We generated mice with macrophage overexpression of mouse LXR-alpha, evidenced by significantly elevated expression levels of LXR-target genes (ABCA1, ABCG1) in these cells. For atherosclerosis studies, mice were crossed onto the LDL-receptor deficient background. Plasma lipids and lipoproteins as well as liver triglycerides were not significantly different between transgenic animals and nontransgenic controls. However, lesion area at the brachiocephalic artery (BCA) was significantly reduced (-83%, P=0.02) in male LXR-alpha transgenic mice. This was associated with a significantly increased cholesterol efflux to acceptor-free media (+24%, P=0.002) and ApoA1 containing media (+20%, P<0.0001) as well as reduced lipopolysaccharide (LPS)-induced NO-release from macrophages of transgenic animals, providing a potential mechanism for the reduction of atherosclerosis. CONCLUSIONS: Our data show for the first time that transgenic overexpression of LXR-alpha in macrophages has significant antiatherogenic properties. We conclude that overexpression of LXR-alpha in macrophages might be useful as a therapeutic principle for the prevention of atherosclerosis.

Effect of macrophage ApoE on atherosclerosis in LDL-receptor deficient mice.

Apolipoprotein E (ApoE) plays an important role in the development of atherosclerosis. Previous studies provide evidence for an atheroprotective role of ApoE in mouse models on the ApoE deficient (ApoE-/-) background. However, it is not clear whether this is also true on the LDL-receptor deficient (LDLR-/-) background. Transgenic mice carrying hApoE coding sequences in a chicken lysozyme expression cassette were generated. Transgene expression was directed into macrophages, expressing low levels of hApoE. Expression of the hApoE transgene was not sufficient to correct hypercholesterolemia. However, lesion area at the brachiocephalic artery (BCA) was significantly reduced (-72%) in female hApoE transgenic mice on the LDLR-/- background. This was associated with increased cholesterol efflux in macrophages of transgenic animals on the ApoE-/- background. We conclude that over-expression of ApoE in macrophages might be useful as a therapeutic principle for the prevention of atherosclerosis.