Lysosome damage

Figure 3. Proposed mechanism for quinone induced apoptosis 5.3.1 Lysosomal damage...

One of the characteristic cellular changes occurring following chemical exposure is the increased fragility of the lysosomal membrane. Lowe el al. (1992) developed an in vitro technique to measure the stability of the lysosomal membrane in isolated liver cells in fish caught in clean and contaminated sites. The technique was based on the ability of cell lysosome to retain neutral red dye. On the basis of this technique, further modifications were implemented by Weeks and Svendsen (1996) to enable use with terrestrial invertebrates. This method (the neutral red retention time assay) has since been applied widely for measuring lysosomal damage. 

Mercury is a reactive element and its toxicity is probably due to interaction with proteins. Mercury has a particular affinity for sulphydryl groups in proteins and consequently is an inhibitor of various enzymes such as membrane ATPase, which are sulphydryl dependent. It can also react with amino, phosphoryl and carboxyl groups. Brain pyruvate metabolism is known to be inhibited by mercury, as are lactate dehydrogenase and fatty acid synthetase. The accumulation of mercury in lysosomes increases the activity of lysomal acid phosphatase which may be a cause of toxicity as lysosomal damage releases various hydrolytic enzymes into the cell, which can then cause cellular damage. Mercury accumulates in the kidney and is believed to cause uncoupling of oxidative phsophorylation in the mitochondria of the kidney cells. Thus, a number of mitochondrial enzymes are inhibited by Hg2+. These effects on the mitochondria will lead to a reduction of respiratory control in the renal cells and their functions such as solute reabsorption, will be compromised. 

Some sensitizers, such as the water-soluble TPPS and AlPcS, localize in lysosomes, which disrupt during PDT [88,89]. The sensitizers are then relocalized in the cells and may even enter the nucleus [89]. Lysosomal damage leads to leakage of the contents of the lysosomes into the cytoplasm. One of the hottest and most promising applications of PDT may turn out to be photochemical internalization the use of PDT to liberate molecules taken up by endosomes and lysosomes (toxins, DNA fragments etc.) into the cytoplasm. Several extremely promising applications of this technique have been proposed and demonstrated [90] since lysosomal disruption in vivo had been demonstrated in 1996 [91]. 

In neuroblastoma cell lines [37,38], HeLa S3 cells [39], and myoblasts [40,46] yessotoxin-induced cell death occurred through apoptosis, associated with activation of caspases. hi the case of myoblasts, formation of apoptotic bodies has also been observed [40], and apoptosis may occur through activation of the mitochondrial pathway [46]. In contrast, apoptosis was not the primary cause of death in IPLB-LdFB and 3T3 cells exposed to yessotoxin, and it was suggested that lysosomal damage was the trigger for cell death in these cells [42]. 

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