Toxicity subcellular targets

Consistent with their role as immune receptors, each human TLR is expressed by at least one subset of myeloid cells (MCs) or lymphocytes [7,8]. TLRs are also present on stromal elements like endothelium particularly after local inflammatory stimulus [9-11]. These distribution patterns can determine the physiological consequences of stimulation or antagonism, and affect the balance of toxicity versus therapeutic effect. Another consideration for medicinal chemistry is subcellular localization of TLRs. While most are expressed on the cell surface, some (TLRs 3,7,8, and 9) can localize to endosomes where they survey ingested material for ligands, so drug access to this compartment can be crucial when targeting these TLRs [12]. 

Dinitrobenzene is an intermediate employed in chemical syntheses of a large number of compounds used in the dye, explosives and plastics industry. The compound is known to induce methemoglobinemia and to cause testicular toxicity with the Sertoli cell being the major target. Nitro reduction was observed in erythrocytes, in rat Sertoli-germ cell cocultures and in rat testicular subcellular fractions, and it was shown that 3-nitrosonitrobenzene was formed that was considerably more toxic. Testicular toxicity was enhanced when the intracellular thiol levels were reduced by pretreatment with diethylmaleate. In turn, pretreatment with cysteamine or ascorbate reduced the toxicity of 1,3-dinitrobenzene and 3-nitrosonitrobenzene. 

Mitochondria were classically considered as the subcellular organelles of eukaryotic cells that produce the energy required to drive the endergonic biochemical processes of cell life. Such a concept is now complemented by the consideration of mitochondria as the most important cellular source of free radicals, as the main target for free radical regulatory and toxic actions, and as the source of signaling molecules that command cell cycle, proliferation, and apoptosis. 

Figure 16.2. Mechanisms of cellular toxicity. Tissues are comprised of cells, and each cell is defined by its cell membrane. The cell membrane is composed of a lipid bilayer, which contains proteins that function as ion channels and receptors. Compounds that disrupt the membrane environment can directly or indirectly alter the normal function of these proteins. In each cell, there are numerous subcellular organelles, all of which are potential targets for toxicity. Cytochrome P450 enzymes in the endoplasmic reticulum may metabolize drugs that enter the cell. Metabolism has one of two effects on the drug s potential toxicity (l)it may reduce toxicity by eliminatingparent compound, or (2) it may increase toxicity by generating a reactive (electrophilic) metabolite. Drugs may inhibit critical functions in mitochondria or damage DNA in the nucleus, which can lead to cell death by apoptosis or necrosis.

This multi-parameter approach provides reliable information to drug discovery teams on the relative toxicity of new compounds in a class, toxicity relative to similar drugs already on the market, STRs, subcellular targets, identification of the mechanism of adverse effects, and plasma concentrations where toxicity would be expected to occur in vivo. 

Nordberg GF, Jin T, Nordberg M. Subcellular targets of cadmium nephrotoxicity cadmium binding to renal membrane proteins in animals with or without protective metallothionein synthesis. Environ Flealth Perspect 1994 102(suppl 3) 191-194. Fowler BA, Akkerman M. The role of Ca + + In cadmium-induced renal tubular cell Injury.. In Cadmium in the human environment toxicity and carcinogenicity. Nordberg G, Herber R, Alessio L (editors). International Agency for Research on Cancer (lARC) Scientific Publications vol 118, Lyon 1992 p. 271-277. 

Effects attributed to chlordane exposure include blood dyscrasia, hepatotoxicity, neurotoxicity, immunotoxicity and cancer. Possible mechanisms of toxicity relevant to all target organs include the ability of chlordane and its metabolites to bind irreversibly to cellular macromolecules, inducing cell death or disrupting normal cell function. In addition, chlordane may increase tissue production of superoxide, which can accelerate lipid peroxidation, disrupting the function of cellular and subcellular membranes. Chlordane induces its own metabolism to toxic intermediates, which may exacerbate its hepatotoxicity. This may involve suppression of hepatic mitochondrial energy metabolism. 

---