In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 97, No. 23 ( 2000-11-07), p. 12770-12775
Abstract:
Hemochromatosis and Wilson disease (WD), characterized by the
excess hepatic deposition of iron and copper, respectively, produce oxidative stress and increase the risk of liver cancer. Because the
frequency of p53 mutated alleles in nontumorous human tissue may be a biomarker of oxyradical damage and identify individuals at increased
cancer risk, we have determined the frequency of p53 mutated alleles in nontumorous liver tissue from WD and hemochromatosis patients. When
compared with the liver samples from normal controls, higher frequencies of G:C to T:A transversions at codon 249
( P 〈 0.001) and C:G to A:T transversions and C:G
to T:A transitions at codon 250 ( P 〈 0.001 and P 〈 0.005) were found in liver tissue from WD
cases, and a higher frequency of G:C to T:A transversions at codon 249 ( P 〈 0.05) also was found in liver tissue from
hemochromatosis cases. Sixty percent of the WD and 28% of hemochromatosis cases also showed a higher expression of inducible
nitric oxide synthase in the liver, which suggests nitric oxide as a source of increased oxidative stress. A high level of etheno-DNA
adducts, formed from oxyradical-induced lipid peroxidation, in liver from WD and hemochromatosis 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 (AGG to AGT). These results are consistent with the
hypothesis that the generation of oxygen/nitrogen species and unsaturated aldehydes from iron and copper overload in hemochromatosis
and WD causes mutations in the p53 tumor suppressor gene.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.220416097
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2000
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
