Hereditary hemochromatosis (HH) is a common autosomal recessive disorder 
characterized by systemic iron overload with consequent tissue damage. The vast 
majority of HH patients are homozygous for the C282Y mutation in HFE, a 
non-classical MHC class-I gene located in chromosome 6, whose role in the 
regulation of systemic iron metabolism is still not completely understood. Iron 
enhances the formation of reactive oxygen species, with increasing risk of DNA 
damage induced by oxidative stress, and consequently an increased susceptibility 
to chromosome instability. In the present work we examined spontaneous and 
diepoxybutane (DEB)-induced chromosome instability in PHA-stimulated lymphocyte 
cultures from 23 HH patients, all homozygous for the C282Y HFE mutation, in 
comparison to 29 normal controls. In addition, three patients with secondary 
forms of iron overload, not related to HFE, were studied as controls to test the 
role of iron overload on DEB-induced chromosome instability. Our results show a 
significantly higher frequency of spontaneous chromosome breaks in lymphocytes 
from the HH patients, when compared with lymphocytes from normal controls 
(p<0.0001). In addition, there is a significant correlation between the 
percentage of cells with spontaneous chromosomal breaks and the transferrin 
saturation (r=0.53, p=0.0041) or serum-ferritin levels (r=0.66, p=0.0001) in 
patients. Surprisingly, the frequency of DEB-induced chromosome breaks was 
significantly lower in lymphocytes from HH patients than in lymphocytes from 
both controls and patients with secondary forms of hemochromatosis (p=0.0029). 
No correlation was observed between the percentage of cells with DEB-induced 
chromosome breaks and the transferrin saturation or serum-ferritin values. These 
results suggest that lymphocytes from HH patients may have an increased capacity 
to respond to DEB-induced chromosome breakage, and that this capacity is somehow 
related to the presence of the C282Y HFE mutation.