Chapter 6 - Cellular copper toxicity: A critical appraisal of fenton-chemistry based oxidative stress in Wilson disease.

The redox activity of copper is of vital importance for biochemical and bioenergetic cellular homeostasis. However, cellular copper overload leads to cell death. Wilson disease patients suffer from such toxic copper overload, especially in their livers. It has been suggested that this accumulating liver copper may catalyze the formation of highly detrimental hydroxyl radicals. However, diverse findings, like the lack of free copper in cells, have challenged such a Fenton-chemistry-based copper toxicity. To weigh these uncertainties, we provide here a survey of studies on oxidative stress markers in WD patients and related animal models and on therapies that aimed at avoiding oxidative stress in WD animals. Collectively, these reports demonstrate that a Fenton-chemistry-based copper toxicity is a concurrent feature with clinically apparent hepatitis in WD animals. However, such oxidative damage is hardly detectable in earlier disease stages, and antioxidative therapies do delay but do not avoid hepatitis. Thus, a Fenton-chemistry-based copper toxicity may be regarded as a major executioner of hepatocyte damage or death, but it does not appear to be the driving toxic mechanism leading to this disease stage