Biological reactive intermediates that mediate chromium (VI) toxicity

Area of Science:

• Hepatotoxicity
• Toxicology
• Biochemistry

Background:

• Hexavalent chromium (Cr VI) is a known toxicant.
• The precise mechanisms underlying Cr VI-induced hepatotoxicity are not fully understood.
• Cr VI exposure can lead to oxidative stress and cellular damage.

Purpose of the Study:

• To investigate the mechanisms of Cr VI-induced cytotoxicity in isolated rat hepatocytes.
• To identify the reactive intermediates involved in Cr VI toxicity.
• To explore the role of cellular redox systems and specific enzymes in Cr VI-induced damage.

Main Methods:

• Isolated rat hepatocytes were exposed to Cr VI.
• Measurements included glutathione oxidation, reactive oxygen species (ROS) formation, lipid peroxidation, and mitochondrial membrane potential.
• The effects of ROS scavengers, antioxidants, glutamine, and specific enzyme inhibitors (cytochrome P450, DT diaphorase, glutathione reductase) were assessed.

Main Results:

• Cr VI rapidly induced glutathione oxidation, ROS formation, lipid peroxidation, and mitochondrial/lysosomal damage prior to cell lysis.
• Cytotoxicity and ROS formation were attenuated by ROS scavengers, antioxidants, glutamine, and cytochrome P450 inhibitors (especially CYP 2E1 inhibitors).
• Hepatocytes with depleted glutathione were resistant to Cr VI toxicity, and Mn II inhibited Cr VI-induced ROS formation, suggesting Cr IV and Cr IV.GSH mediate ROS production.

Conclusions:

• Cr VI-induced hepatotoxicity is mediated by reactive intermediates, specifically Cr IV and ROS.
• Mitochondrial and lysosomal dysfunction are key events in Cr VI cytotoxicity.
• Cytochrome P450 enzymes, particularly CYP 2E1, appear to play a role in the reductive activation of Cr VI to toxic intermediates.