The fluroxene mediated degradation of cytochromes P-450

The degradation of cytochromes P-450 by fluroxene (2,2,2-trifluoroethyl vinyl ether) has been investigated. Fluroxene is shown to specifically degrade cytochromes P-450 in vivo and in vitro without affecting the levels of the other microsomal enzymes, cytochrome ~S a.nd NADPH-cytochrome~ reductase. Fluroxene appears to degrade the haem moiety of cytochromes P-450 but does not affect the level of the apoprotein. The degradation of cyto-chromes P-450 by fluroxene is accompanied by a loss of E-nitroanisole 0-demethylase and biphenyl 4-hydroxylase activities and a decrease in the extent of aniline binding is observed. By using cytochromes P-450 dependent reactions which are catalysed by specific type P-450 cytochromes,~.~· the hydroxylation of benzpyrene, the N-demethylation of ethyl-morphine and the binding of ethyl isocyanide, it is established that only cytochrome P-450 is degraded by fluroxene in vivo following phenobarbital induction of animals, and both cytochrome P-450 and cytochrome P-448 following methylcholanthrene induction. The same type P-450 cytochromes are shown to be degraded by fluroxene in vitro in phenobarbital and methylcholanthrene induced microsomes. This was established from studies of the kinetics of the fluroxene mediated degradation of cyto-chromes P-450. In addition, the K values for the flurox-m ene mediated degradation of cytochromes P-450 differ with iii the different inducing agents and indicate the involve-ment of two different type P-450 cytochromes in the degradation reaction in methylcholanthrene induced micro-somes. Metabolic activation of cytochromes P-450 by the cyto-chromes P-450 drug metabolising pathway appears to be essential for the fluroxene mediated degradation of cyto-chromes P-450. Since none of the known or proposed metabolites of fluroxene can mimic the degradation of cytochromes P-450 by fluroxene, a reactive species is proposed to be involved. By varying the experimental conditions, and with the use of inhibitors of cytochromes P-450, the likely sequence of events in the fluroxene mediated degradation of cytochromes P-450 is shown to be as follows: fluroxene is metabolised by cytochrome P-450 to a transient reactive intermediate which has the ability to degrade the haem moiety of cytochrome P-450 and cyto-chrome P-448. By comparing the ability of various analogues of fluroxene to degrade cytochromes P-450, it is established that the formation of the proposed reactive intermediate is dependent on the presence of the vinyl moiety of the molecule. Initial studies indicate that the reactive species may take the form of an epoxide

Development of biomimetic catalytic oxidation methods and non-salt methods using transition metal-based acid and base ambiphilic catalysts

This review focuses on the development of ruthenium and flavin catalysts for environmentally benign oxidation reactions based on mimicking the functions of cytochrome P-450 and flavoenzymes, and low valent transition-metal catalysts that replace conventional acids and bases. Several new concepts and new types of catalytic reactions based on these concepts are described

Role of cytochrome P-450 as a source of catalytic iron in cisplatin-induced nephrotoxicity

Role of cytochrome P-450 as a source of catalytic iron in cisplatin-induced nephrotoxicity.BackgroundIron plays a role in free radical-mediated tissue injury, including cisplatin-induced nephrotoxicity. However, the source of iron (catalyzing free radical reactions) is not known. We examined the role of cytochrome P-450 as a source of catalytic iron in cisplatin-induced nephrotoxicity both in vivo and in vitro.MethodsCisplatin-induced acute renal failure was produced in rats by intraperitoneal injection of cisplatin (10mg/kg body wt). Piperonyl butoxide, a cytochrome P-450 inhibitor, was administered intraperitoneally (400mg/kg body wt twice at 48-hr intervals) prior to cisplatin injection. The effects of cisplatin in the absence or presence of piperonyl butoxide on the belomycin-detectable iron, cytochrome P-450 content in the kidney, and renal functional and histological changes were evaluated. In an in vitro study, the effect of cytochrome P-450 inhibitors, cimetidine or piperonyl butoxide, on cisplatin-induced cytotoxicity and catalytic iron release from LLC-PK1 cells was examined.ResultsIn cisplatin-treated rats, there was a marked decrease in the cytochrome P-450 content specifically in the kidney, accompanied by increased bleomycin-detectable iron content in the kidney. Piperonyl butoxide prevented cisplatin-induced loss of cytochrome P-450 as well as the increase of bleomycin-detectable iron in the kidney, along with both functional and histological protection. Both cimetidine and piperonyl butoxide prevented cisplatin-induced increase in bleomycin-detectable iron and cytotoxicity in LLC-PK1 cells. Treatment of cimetidine did not affect cellular uptake of cisplatin.ConclusionCytochrome P-450, a group of heme proteins, may serve as a significant source of catalytic iron in cisplatin-induced nephrotoxicity

Model Calculations for the Two-Fragment Electro-Disintegration of 4^4He

Differential cross sections for the electro-disintegration process $e + {^4He} \longrightarrow {^3H}+ p + e'$ are calculated, using a model in which the final state interaction is included by means of a nucleon-nucleus (3+1) potential constructed via Marchenko inversion. The required bound-state wave functions are calculated within the integrodifferential equation approach (IDEA). In our model the important condition that the initial bound state and the final scattering state are orthogonal is fulfilled. The sensitivity of the cross section to the input $p{^3H}$ interaction in certain kinematical regions is investigated. The approach adopted could be useful in reactions involving few cluster systems where effective interactions are not well known and exact methods are presently unavailable. Although, our Plane-Wave Impulse Approximation results exhibit, similarly to other calculations, a dip in the five-fold differential cross-section around a missing momentum of $\sim 450 MeV/c$, it is argued that this is an artifact of the omission of re-scattering four-nucleon processes.Comment: 16 pages, 6 figures, accepted for publication by Phys.Rev.

Observing Non-Gaussian Sources in Heavy-Ion Reactions

We examine the possibility of extracting non-Gaussian sources from two-particle correlations in heavy-ion reactions. Non-Gaussian sources have been predicted in a variety of model calculations and may have been seen in various like-meson pair correlations. As a tool for this investigation, we have developed an improved imaging method that relies on a Basis spline expansion of the source functions with an improved implementation of constraints. We examine under what conditions this improved method can distinguish between Gaussian and non-Gaussian sources. Finally, we investigate pion, kaon, and proton sources from the p-Pb reaction at 450 GeV/nucleon and from the S-Pb reaction at 200 GeV/nucleon studied by the NA44 experiment. Both the pion and kaon sources from the S-Pb correlations seem to exhibit a Gaussian core with an extended, non-Gaussian halo. We also find evidence for a scaling of the source widths with particle mass in the sources from the p-Pb reaction.Comment: 16 pages, 15 figures, 5 tables, uses RevTex3.