Superfund Research Program
Biological Dosimetry of Hexavalent Chromium
Project Leader: Anatoly Zhitkovich
Grant Number: P42ES013660
Funding Period: 2005-2014
Studies and Results
Hexavalent chromium is a widespread environmental carcinogen that is found at more than 100 Superfund sites. Once taken up by cells, chromium-6 undergoes reductive activation to chromium-3, which is responsible for the formation of mutagenic DNA damage and gross chromosomal abnormalities. In contrast, extracellular reduction of chromium-6 is a detoxification process producing cell-impermeable chromium-3. Human exposure to chromium-6 is commonly associated with ingestion or inhalation of other cancer-causing metals due to their co-presence at the majority of toxic waste sites. An important strategy for avoidance of adverse health effects due to exposure to toxic metals could be the use of chemopreventive agents that can suppress the ability of metals to cause genetic damage and other forms of biological injury. The researchers conducted detailed studies to evaluate a potential utility of N-acetylcysteine as a chemopreventive agent against chromium-6 and two other toxic and carcinogenic metals, cadmium and cobalt (Luczak M.W., A. Zhitkovich. 2013. Role of direct reactivity with metals in chemoprotection by N-acetylcysteine against chromium(VI), cadmium(II), and cobalt(II). Free Radical Biology & Medicine. 65:262-269. [Abstract]). N-acetylcysteine is generally known as a free radical scavenger that is used clinically for treatment of acetaminophen overdosing. The researchers found that N-acetylcysteine was very effective in protection of human cells against various toxic effects of all three metals, including such sensitive toxicity measures as activation of stress-responsive transcriptional factors, energy-generating mitochondrial activity, and long-term reproductive potential of cells. Unlike its activity against acetaminophen toxicity when N-acetylcysteine acts inside the cells, protective processes against metals principally occurred outside the cells and involved blocking the cellular entry of these toxicants. Inhibition of cellular accumulation of metals by N-acetylcysteine provided an explanation for its ability to effectively prevent all forms of cellular toxicity. Failure of toxic metals to be taken up by human cells in the presence of N-acetylcysteine resulted from the production of metal forms that were unable to cross cellular membranes. Examinations of N-acetylcysteine reactions allowed the researchers to identify specific chemical processes that led to loss of cell penetration by toxic metals. In the case of chromium-6, N-acetylcysteine catalyzed its conversion to cell-impermeable chromium-3. Reaction of N-acetylcysteine with cobalt and cadmium caused chelation (sequestration) of these metals and the resulting complexes lacked the ability to enter cells.
The researchers' studies identified an antioxidant-independent mechanism for chemoprotection by N-acetylcysteine against chromium-6 and two other carcinogenic metals, cobalt and cadmium. Bioinactivation of metals by N-acetylcysteine outside the cells provides a strong protection against cellular accumulation of these ubiqiuotous toxicants, which is responsible for adverse health effects of chronic, low-dose environmental exposures and is difficult to recognize and treat.