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

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 oxygen͞ nitrogen species and unsaturated aldehydes from iron and copper overload in hemochromatosis and WD causes mutations in the p53 tumor suppressor gene.Wilson disease ͉ hemochromatois ͉ p53 ͉ iron ͉ copper ͉ liver carcinogenesis

The p53 network in lung carcinogenesis

“…p53 mutations and protein stabilization have been observed in preneoplastic lesions, such as bronchial epithelial dysplasia Sozzi et al, 1992;Sundaresan et al, 1992;Vahakangas et al, 1992). Recently, p53 mutations were found in nontumorous peripheral lung tissue from lung cancer patients, supporting their role in the etiology of lung cancer (Hussain et al, 2001).…”

“…A high frequency of G to T transversions at codons 157 and 249 of p53 was found in nontumorous peripheral lung tissue in lung cancer cases among smokers (Hussain et al, 2001). Interestingly, codon 157 mutations are infrequent in other cancers, including lung cancers from never-smokers (Hainaut and Pfeifer, 2001).…”

“…More de®nitive validation of the role of BPDE as a carcinogen that shapes the p53 mutational spectrum in lung cancers comes from the evaluation of the p53 mutational load in nontumorous lung tissue (Hussain et al, 2001). A high frequency of G to T transversions at codons 157 and 249 of p53 was found in nontumorous peripheral lung tissue in lung cancer cases among smokers (Hussain et al, 2001).…”

Stress-induced corneal epithelial apoptosis mediated by K+ channel activation

“…For example, one of its roles is to act as a tumor suppressor protein that senses DNA damage and acts as a guardian of genome stability (Chernova et al, 1995;Blaise et al, 2001;Gentiletti et al, 2002). In some cases, p53 becomes a molecular signature based on the type of cancer (Hussain et al, 2000). The multiple functions of p53 include: (1) to regulate cell-cycle progression; (2) to survey cellular stress; and (3) to induce apoptosis in extreme cases.…”

Non-Hfe Iron Overload: Is Phlebotomy the Answer?

“…In well-compensated cirrhosis, the presence of stainable Fe on liver biopsy may be predictive of more rapid deterioration in liver function compared with patients without siderosis [28]. An excess of hepatocellular Fe generates ROS that cause lysosomal fragility [29], mitochondrial dysfunction [30] via lipid peroxidation of organelle membranes, resulting in the formation of protein and DNA adducts and mutation [31]. Usual cellular protective mechanisms are overwhelmed in Fe overload states leading to apoptosis and cell necrosis.…”