a comparison of hepatocyte cytotoxic mechanisms for docetaxel and plga-docetaxel nanoparticls

Authors

marjan aghvami department of toxicology, faculty of medical sciences, tarbiat modares university, tehran, iran

jalal pourahmad faculty of pharmacy, department of toxicology & pharmacology, shaheed beheshti university of medical sciences, iran

rassoul dinarvand nanotechnology research centre, faculty of pharmacy, university of medical sciences, tehran, iran

bahram daraei department of toxicology, faculty of medical sciences, tarbiat modares university, tehran, iran

abstract

docetaxel (dtx) is one of the most widely used drugs in oncology due to its high efficacy against several cancers. though, its routine clinical administration, formulated in tween 80, causes serious side effects. polylactide-co-glycolide (plga), biodegradable polyester synthesized and approved for human use, is employed to overcome this problem. in this investigation, we compare the cytotoxic mechanisms of dtx and plga-dtx in isolated rat hepatocytes. cytotoxicity of dtx and plga-dtx were associated with reactive oxygen species formation, activation of caspases cascade, collapse of mitochondrial membrane potential (mmp), lysosomal membrane leakiness and atp depletion. our results also showed that cyp2e1 is involved in the oxidative stress cytotoxicity mechanism and both drugs are detoxified via phase ii metabolic methylation. furthermore, we concluded that plga-dtx is bioactivated by gsh. it could also potentiate hepatocyte toxicity through a mitochondrial/lysosomal toxic cross-talk. in addition to these observed differences, it is likely that mode of hepatocyte membrane penetration is different between these compounds.

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Journal title:
iranian journal of pharmaceutical research

جلد ۱۶، شماره ۱، صفحات ۲۴۹-۲۶۵

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