1. The effect of the aromatic solvents toluene, xylene and ethylbenzene on microsomal membrane fluidity and anaerobic NADPH-reduction kinetics were studied. 2. The relation of membrane fluidity to the kinetics of cytochrome P450 reduction by NADPH-cytochrome P450 reductase was examined with regard to a membrane-mediated molecular organization of the multienzyme components of the monooxygenase system. 3. Membrane fluidity changes were detected with the steady-state pyrene excimer formation method and with fluorescence lifetime measurements after incubation of the microsomes with organic solvents. 4. Increase in membrane fluidity in presence of organic solvents leads to a small but significant decrease of the rate constant of the cytochrome P450 reduction kinetics and a change in the relative amplitudes of the components of the biphasic response. 5. The results support the idea of a molecular organization of cytochrome P450 in clusters. Fluidization of the microsomal membrane by organic solvents increase the cytochrome P450 cluster formation.
[Show abstract][Hide abstract] ABSTRACT: Organ transplantation is an accepted therapy for diseases that result in chronic irreversible failure of various organs. During transplantation, the transplanted organ is subjected to two inflammatory processes, alloantigen-independent (ischemia/reperfusion injury) and alloantigen-dependent (rejection), both of which involve release of cytokines. The objectives of this dissertation were to evaluate the effect of acute rejection of liver in rats on hepatic and extra-hepatic drug metabolizing capacity for phase I and II enzymes, to evaluate the effect of chronic rejection of liver in humans on hepatic metabolizing capacity of phase I and II enzymes, to evaluate the effect of acute and chronic rejection of liver on hepatic and extra-hepatic protein and mRNA expression of P-glycoprotein and to evaluate the effect of different cytokines on the constitutive and inducible hepatic CYP3A4 activity and protein expression in human hepatocytes. Alloantigen-independent inflammation and altered blood flow caused a reduction in hepatic mRNA of different phase I and II enzymes. However, this reduction did not significantly alter protein levels of all CYP450 enzymes studied. Occurrence of rejection resulted in further reduction in mRNA, protein levels and activity of all CYP450s studied. Syngeneic and allogeneic transplantation caused reduction in the metabolic capacity of extra-hepatic tissues and increased expression of P-gp in the liver. Chronic rejection of the liver in humans selectively altered the activity and protein expression of different phase I and II enzymes and increased P-gp protein expression. In human hepatocyte cultures, IL-1â, IL-6 and TNF-á decreased the activity and protein expression of both constitutive and induced forms of CYP3A4 enzyme. Pre-exposing or co-exposing the hepatocytes to cytokines reduced the ability of rifampicin to induce CYP3A4.In conclusion, acute and chronic rejection of liver significantly altered the expression and activity of several drug metabolizing enzymes and transporters. The magnitude of these alterations was higher in acute rejection. Acute rejection also caused alterations in the metabolizing ability and transporters expression in renal and pulmonary tissues. Cytokines play a major role in modulating the activity of drug metabolizing enzymes and transporters and may contribute to the large inter-individual variation in the pharmacokinetics of drugs in transplant patients.
[Show abstract][Hide abstract] ABSTRACT: The authors describe a decoding scheme and erase sequence for a
5-V-only sector-erasable flash memory. A source line decoder eliminates
the erase disturb problem and lowers the power consumption. The maximum
switching voltage is reduced to 10 V, which makes possible a tight word
line pitch for a 64-Mb flash memory. Narrow threshold voltage
distribution of erased memory cells is obtained by programming after
[Show abstract][Hide abstract] ABSTRACT: A brief literature review shows that ionizing radiation in biological membranes and in pure lipid membranes causes malondialdehyde formation, indicating lipid peroxidation processes. With respect to membrane fluidization by ionizing radiation, in pure lipid membranes rigidization effects are always reported, whereas contradictory results exist for biological membranes. Starting from the assumption that membrane proteins at least partly compensate for radiation effects leading to a rigidization of membrane lipid regions, pig liver microsomes, as a representative protein-rich intracellular membrane system, were irradiated with X-rays or UV-C with doses up to 120 Gy at a dose rate of 0.67 Gy min-1 and up to 0.73 J cm-2 at an exposure rate of 16.2 mJ cm-2 min-1, respectively. For both irradiation types a weak but significant positive correlation between malondialdehyde formation and membrane fluidity is revealed throughout the applied dose ranges. We conclude that the membraneous protein lipid interface increases its fluidity under radiation conditions. Also, thymocyte ghosts showed an increased fluidity after X-ray irradiation. Fluidity measurements were performed by the pyrene excimer method.
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