Eukaryotic cell toxicity

Compounds that show general eukaryotic cell toxicity may give rise to false positives, or show nonspecific activity, in cell-based assays. (Some of these also act by damaging membranes and may overlap with the detergent-like class of compounds.)... 

An effective way to test eukaryotic cell toxicity is to study the haemolytic behaviour of a system. While not conclusive, haemolysis experiments are used to indicate the possibility of eukaryotic cell toxicity [50]. It was found that, at the highest concentration tested (3 mg/ml), minimal haemolysis was observed. The high selectivity of these polymers is attributed to the use of fully water-soluble monomers, which allow the incorporation of hydrophobic moieties while maintaining the water-solubility of the polymer. A common practice within the antimicrobial polymer community is to report polymer selectivity toward bacterial cells over eukaryotic cells as a ratio of... 

Protein phosphatases are ubiquitous. They are foxmd in all tissues and across species as diverse as mammals, plants, and bacteria, and they play a critical role in the regulation of multiple cellular metabolic pathways. Protein phosphatases reverse tiie active state of kinases through the hydrolytic removal of tiie phosphoryl group from kinases. The protein phosphatases inhibited by microcystins have broad substrate specificity and play roles in the regulation of a wide range of cellular fxmc-tions. Protein phosphatase 2A is highly conserved and is a major downregulator of active protein kinases in eukaryotic cells. Toxic effects in hepatocytes and other... 

Bacitracin (Fig. 4) is a cyclic peptide antibiotic. The lipid II molecule involved in the bacterial cell wall biosynthesis has a C55 isoprenyl pyrophosphate moiety that must be dephosphorylated so that it can reparticipate in another round of lipid II transfer. Bacitracin binds to the isoprenyl pyrophosphate and prevents the dephosphorylation which, in turn, blocks cell wall growth by interfering with the release of the muropeptide subunits to the outside of the bacterial cell membrane. Bacitracin inhibits similar reactions in eukaryotic cells. So, it is systemically toxic but is an effective and widely used topical antibiotic. 

Protein synthesis is a central function in cellular physiology and is the primary target of many naturally occurring antibiotics and toxins. Except as noted, these antibiotics inhibit protein synthesis in bacteria. The differences between bacterial and eukaryotic protein synthesis, though in some cases subtle, are sufficient that most of the compounds discussed below are relatively harmless to eukaryotic cells. Natural selection has favored the evolution of compounds that exploit minor differences in order to affect bacterial systems selectively, such that these biochemical weapons are synthesized by some microorganisms and are extremely toxic to others. Because nearly every step in protein synthesis can be specifically inhibited by one antibiotic or another, antibiotics have become valuable tools in the study of protein biosynthesis. 

For oligonucleotide delivery to eukaryotic cells compound GS2888 (Figure 15.17) was synthesized by Lewis et al. (1996). This compound can be used both in the presence and absence of serum with high reproducibility and minimal toxicity. 

Ricin is a type II toxin. The A chain (ricin A) contains 267 amino acid residues, and the B chain (ricin B) 262 residues. Ricin A is exceptionally toxic, and it has been estimated that a single molecule is sufficient to kill an individual cell. This peptide can be prepared by genetic engineering using Escherichia coli. The potent action of this material on eukaryotic cells has been investigated in anticancer therapy. Ricin A has been coupled to monoclonal antibodies and successfully delivered specifically to the tumour cells. However, in vitro toxicity of ricin A-based immunotoxins is enhanced significantly if ricin B is also present. 

Cu—Zn superoxide dismutases (SODs) [87,88] are abundant in eukaryotic cells and may serve to protect cells against the toxic effects of superoxide or deleterious oxy-products derived from 02 . The active site copper and zinc ions are 6.3 A apart and are bridged by a histidine imidazolate. In the oxidized form Cu(II) is roughly pentacoordinate, with four His N s and a water molecule. A highly conserved Arg residue is thought to stabilize Cu(II)-bound anions (e.g., Cu(II)—02 ) a redox reaction releases 02, generating Cu(I), which can reduce more 02 substrate to give peroxide and Cu(II). 

The nuclei of eukaryotic cells contain multiply coiled DNA bound with proteins in bodies called chromosomes. The number of chromosomes varies with the organism. Humans have 46 chromosomes in their body cells (somatic cells) and 23 chromosomes in each germ cell, the eggs and sperm that fuse to initiate sexual reproduction. During cell division, each chromosome is duplicated and the DNA in it is said to be replicated. The production of duplicates of a molecule as complicated as DNA has the potential to go wrong and is a common mode of action of toxic substances. Uncontrolled cell duplication is another problem that can be caused by toxic substances and can result in the growth of cancerous tissue. This condition can be caused by exposure to some kinds of toxicants. 

MICROSOME A phospholipid-nucleoprotein complex derived from the ribosomes and endoplasmic reticulum of eukaryotic cells site of diverse enzymatic reactions important in the metabolism of toxicants and other chemicals. 

Chemotherapy based on selective toxicity was first conceived by Paul Ehrlich. It relied on the principle that the drug should be more toxic and harmful for the invading microorganism than for the host. This understanding rendered the phenolic compounds and alcohols unsatisfactory as chemotherapeutic agents, since they caused considerable damage to the eukaryotic cells and their natural defense mechanisms. 

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