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 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.
Hussain
S P
SP
Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Raja
K
K
Amstad
P A
PA
Sawyer
M
M
Trudel
L J
LJ
Wogan
G N
GN
Hofseth
L J
LJ
Shields
P G
PG
Billiar
T R
TR
Trautwein
C
C
Hohler
T
T
Galle
P R
PR
Phillips
D H
DH
Markin
R
R
Marrogi
A J
AJ
Harris
C C
CC
D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D003300:Copper / Q000378:metabolism; D005609:Free Radicals; D005805:Genes, MHC Class I; D006680:HLA Antigens / Q000235:genetics; D006432:Hemochromatosis / Q000235:genetics* / Q000473:pathology; D000071020:Hemochromatosis Protein; D006527:Hepatolenticular Degeneration / Q000235:genetics* / Q000473:pathology; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins; D016296:Mutagenesis / Q000187:drug effects; D009154:Mutation; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D011817:Rabbits; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D000447:Aldehydes; D005609:Free Radicals; C103673:HFE protein, human; D006680:HLA Antigens; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D016159:Tumor Suppressor Protein p53; D003300:Copper; D007501:Iron; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C027576:4-hydroxy-2-nonenal