Paper Information

Title: 

A SEARCH FOR MOLECULAR MECHANISMS RESPONSIBLE FOR CR (VI) INDUCED CYTOTOXICITY

Type: SPEECH
Author(s): POURAHMAD J.,SHAKOORI A.
 
 
 
Name of Seminar: IRANIAN CONGRESS OF TOXICOLOGY
Type of Seminar:  CONGRESS
Sponsor:  SOCIETY OF TOXICOLOGY
Date:  2004Volume 8
 
 
Abstract: 

Chromate (Cr (VI)) is an environmental and occupational carcinogen and may induce lung or kidney cancer. Acute or chronic adminestration of chromate induces hepatic toxicity in rodents. It is postulated that oxidative stress is involved in chromate induced cytotoxicity.
In the following we have investigated the cytotoxicity mechanisms of the oxyanion chromate.
We have used isolated rat hepatocytes as an cellular model for cytotoxicity studies .To investigate chromate induced cytotoxicity, reactive oxygen species (ROS) formation, mitochondrial membrane potencial decline, lysosomal membrane damage and fate of intracellular glutathione were measured using well-known spectrofluorimetric methods.
Chromate cytotoxicity was associated with (ROS) formation, lipid peroxidation and loss of mitochondrail membrane potential, which were prevented by catalase, antioxidants and ROS scavengers. Hepatocytes glutathione was rapidly oxidized. Chromate reduction was inhibited in glutathione depleted hepatocytes and glutathione depleted hepatocytes were also much more resistant to chromate induce cytotoxicity, ROS formation and lipid peroxidation. Inhibitors of cytochrom P450 or P450 reductase prevented chromate induced cytotoxicity and ROS formation. This suggests that chromate is reductively activated by both glutathione and cytochrom P450. Chromate cytotoxicity also involved lysosomal injury and protease activation which were prevented by lysosomotropic agents, endocytosis inhibitors, protease inhibitors and ROS scavengers. In conclusion chromate induced cytotoxicity could be attributed to oxidative stress and lysosomal damage.

 
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