Increased p53 mutation load in nontumorous human liver of Wilson disease and hemochromatosis: Oxyradical overload diseases

Hemochromatosis and Wilson disease (WD), characterized by the excess hepati c deposition of iron and copper, respectively, produce oxidative stress and increase the risk of liver cancer. Because the frequency of p53 mutated al leles in nontumorous human tissue may be a biomarker of oxyradical damage a nd identify individuals at increased cancer risk, we have determined the fr equency of p53 mutated alleles in nontumorous liver tissue from WD and hemo chromatosis patients. When compared with the liver samples from normal cont rols, higher frequencies of G:C to T:A transversions at codon 249 (P < 0.00 1) and C:G to A:T transversions and C:C to T:A transitions at codon 250 (P < 0.001 and P < 0.005) were found in liver tissue from WD cases, and a high er frequency of G:C to T:A transversions at codon 249 (P < 0.05) also was f ound in liver tissue from hemochromatosis cases. Sixty percent of the WD an d 28% of hemochromatosis cases also showed a higher expression of inducible nitric oxide synthase in the liver, which suggests nitric oxide as a sourc e of increased oxidative stress. A high level of etheno-DNA adducts, formed from oxyradical-induced lipid peroxidation, in liver from WD and hemochrom atosis patients has been reported previously. Therefore, we exposed a wild- type p53 TK-6 lymphoblastoid cell line to 4-hydroxynonenal. an unsaturated aldehyde involved in lipid peroxidation, and observed an increase in G to T transversions at p53 codon 249 (ACC to AGT). These results are consistent with the hypothesis that the generation of oxygen/ nitrogen species and uns aturated aldehydes from iron and copper overload in hemochromatosis and WD causes mutations in the p53 tumor suppressor gene.