Toxicity cell membrane permeability

The mechanisms of kidney injury include direct tubular epithelial cell toxicity with increased tubular permeability and necrosis, as well as arterial vasoconstriction and ischemic injury (Fanos and Cataldi 2000). Overall, the combined effects of increased cell energy and oxygen requirements due to greater cell membrane permeability, and reduced cellular oxygen delivery due to renal vasoconstriction, results in renal medullary tubular epithelial cell necrosis and kidney injury. Risk factors include CKD, higher average daily doses, volume depletion, and concomitant administration of diuretics and other nephrotoxins (e.g., cyclosporine) (Deray 2002 Costa and Nucci 2001). Rapid infusions of amphotericin B have the potential... 

Quite generally, the interphase between an organism and its environment encompasses the elements outlined in Figure 1 of Chapter 1. The scheme shows that the cell membrane, with its hydrophobic lipid bilayer core, has the most prominent function in separating the external aqueous medium from the interior of the cell. The limited and selective permeabilities of the cell membrane towards components of the medium - nutrients as well as toxic species - play a governing role in the transport of material from the medium towards the surface of the organism. 

Hormesis, in which compensatory adaptive changes precede and occur at lower doses than degenerative changes, was detected for half of the toxic drugs for cell proliferation, cell morphology and mitochondria [4, 33]. Hormesis could not be assessed for parameters that normally have low values, such as intracellular calcium measured by fluo4 or membrane permeability measured by toto-3, because assay methods were not sufficiently sensitive. However, for calcium, more sensitive dyes. 

The effects of a chemical in a tissue frequently depend on the chemical s interaction with cell surface or cytoplasmic receptors. In some cases, a chemical interacts directly with the cell membrane and alters its permeability. The pharmacodynamic actions of drugs are usually mediated by interactions with a receptor, and a drug often competes with endogenous ligands of a receptor. The toxicity of environmental chemicals can also depend on and be mediated by interactions with receptors. In some cases, the responses are different for chemical exposures at different fetal stages of development, and it is possible to explain the different responses by the chronology of the development of fetal receptor systems. The fetus may develop receptor systems for a compound before it develops the ability to metabolize that compound thus, a low level of an active chemical can have greater and more persistent effects in the fetus than in the mother, whose metabolism limits the duration and extent of the effect. This is one mechanism for selective developmental toxicity of chemicals. 

This process is an early morphological change in cells often seen in isolated cells in vitro but also known to occur in vivo. The blebs, which appear before membrane permeability alters, are initially reversible. However, if the toxic insult is sufficiently severe and the cellular changes become irreversible, the blebs may rupture. If this occurs, vital cellular components may be lost and cell death follows. The occurrence of blebs may be due to damage to the cytoskeleton, which is attached to the plasma membrane as described above. The cause may be an increase in cytosolic Ca2+, interaction with cytoskeletal proteins, or modification of thiol groups (see below). 

It is not surprising then that, despite its effectiveness, methotrexate therapy is underscored by serious side-effects and problems which have prompted ongoing research programmes to attempt the preparation of new analogues possessing better tumour-cell selectivity, lower toxicity, better transport properties, and improved lipid solubility and membrane permeability. These efforts have resulted in the preparation of thousands of analogues in which virtually every major area of the molecule has been varied and evaluated. 

The permeability, P (P = Pc x D), of a nonpolar substance through a cell membrane is dependent on two physicochemical factors (1) solubility in the membrane (Pc), which can be expressed as a partition coefficient of the drug between the aqueous phase and membrane phase, and (2) diffusivity or diffusion coefficient (D), which is a measure of mobility of the drug molecules within the lipid. The latter may vary only slightly among toxicants, but the former is more important. Lipid solubility is therefore one of the most important determinants of the pharmacokinetic characteristics of a chemical, and it is important to determine whether a toxicants is readily ionized or not influenced by pH of the environment. If the toxicant is readily ionized, then one needs to understand its chemicals behavior in various environmental matrices in order to adequately assess its transport mechanism across membranes. 

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