Ischemic preconditioning protects from hepatic ischemia/reperfusion-injury by preservation of microcirculation and mitochondrial redox-state.

Background/aims: Ischemic preconditioning (IP) is known to protect hepatic tissue from ischemia-reperfusion injury. However, the mechanisms involved are not fully understood yet.

Methods: Using intravital multifluorescence microscopy in the rat liver, we studied whether IP exerts its beneficial effect by modulating postischemic Kupffer cell activation, leukocyte-endothelial cell interaction, microvascular no-reflow, mitochondrial redox state, and, thus, tissue oxygenation.

The influence of CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent antioestrogen Z-4-hydroxy-tamoxifen in human liver.

Aims: To investigate in a large panel of 50 human liver samples the contribution of CYP2C9, CYP2D6, and CYP3A4 to the overall formation of the potent antioestrogen Z-4-hydroxy-tamoxifen, and how various genotypes affect its formation from tamoxifen.

Methods: The formation of Z-4-hydroxy-tamoxifen from 10 microm tamoxifen was studied in human liver microsomes (n=50), characterized for CYP2B6, CYP2C9, CYP2D6 and CYP3A4 expression, and CYP2B6, CYP2C9 and CYP2D6 genotype. The effect of chemical and monoclonal antibody inhibitors, and the formation in supersomes expressing recombinant CYP isoforms was also investigated.

Adenovirus-mediated gene transfer of P16INK4/CDKN2 into bax-negative colon cancer cells induces apoptosis and tumor regression in vivo.

The tumor-suppressor gene p16INK4/CDKN2 (p16) is a cyclin-dependent kinase (cdk) inhibitor and important cell cycle regulator. Here, we show that adenovirus-mediated gene transfer of p16 (AdCMV.p16) into colon cancer cells induces uncoupling of S phase and mitosis and subsequently apoptosis.

Genetic polymorphisms of glutathione S-transferase A1, the major glutathione S-transferase in human liver: consequences for enzyme expression and busulfan conjugation.

Background: High-dose busulfan is widely used as part of conditioning regimens for patients who are undergoing hematopoietic stem cell or bone marrow transplantation. High plasma concentrations of busulfan have been linked to the occurrence of hepatic venoocclusive disease (VOD), a severe complication associated with a high mortality. Because conjugation with glutathione, the major route of biotransformation of busulfan, is predominantly catalyzed by the isozyme glutathione S-transferase A1 (GSTA1), we hypothesized that low expression or function of GSTA1 in liver caused by genetic polymorphisms may be the mechanism underlying VOD.

Inhibition of nitric oxide synthase does not influence urinary nitrite plus nitrate excretion after renal ischemic injury.

Background And Aims: Whether renal nitric oxide production caused by ischemia/reperfusion (I/R) influences the urinary excretion of nitric oxide (NO) metabolites (nitrite and nitrate) is far from being elucidated. In the present study, we evaluated the role of NO synthase inhibition using N(G)-nitro- L-arginine methyl ester ( L-NAME) in a model of experimental renal I/R injury.

Methods: Male Wistar rats were used in our experiments, and renal I/R injury was achieved after a 30-min occlusion of the bilateral renal artery followed by a 60-min period of reperfusion.

Cardiac and renal effects of growth hormone in volume overload-induced heart failure: role of NO.

Growth hormone (GH) application is a new strategy in the treatment of heart failure. However, clinical and experimental investigations have shown contradictory effects of GH on cardiac performance. We tested the hypothesis that GH could improve cardiac and renal function in volume overload-induced heart failure.

Discriminative quantification of cytochrome P4502D6 and 2D7/8 pseudogene expression by TaqMan real-time reverse transcriptase polymerase chain reaction.

The human drug oxidizing cytochrome P450, CYP2D6, is expressed at highly variable levels mainly due to a common genetic polymorphism which leads to the poor metabolizer phenotype in carriers of two nonfunctional alleles and to the extensive metabolizer phenotype in carriers of one or more functional alleles. Investigation of the role of CYP2D6 mRNA for expression and the possibility of using mRNA expression as a surrogate marker has been hampered by the presence of two pseudogenes, CYP2D7P and CYP2D8P. We therefore developed highly specific TaqMan real-time reverse transcriptase-PCR assays for the discriminative quantification of CYP2D6 and CYP2D7/8P transcripts.