PubMed · 10048946
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G A Boorman. 1998. EMF working group.. https://doi.org/10.1289/ehp.106-1533239
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OBJECTIVE: To study the dynamic change of glutathione S- transferase pi (GST-pi) in normal gastric mucosa, gastric mucosa with intestinal metaplasia (IM) and gastric cancer and to investigate the relationship between human carcinogen detoxification system and the virulence of Helicobacter pylori(H.pylori) in the stage of IM. METHODS: Two hundred and nineteen biopsy specimens of gastric mucosa, including 30 cases with normal gastric mucosa, 171 cases with IM and 18 cases with gastric cancer, were examined. The expression of GST-pi was detected by S-P immunohistochemical method. High-iron diamine /alcian blue pH2.5/periodic acid -Schiff (HID-ABpH 2.5-PAS) method was used to classify IM. H.pylori infection was confirmed or excluded by hematoxylin-eosin (HE) staining, of H.pylori-DNA PCR and ELISA. The 80 cases with H.pylori infection were treated by bismuthate + amoxicillin + metronidazole for three months and then biopsy specimens were taken again from the original sites. RESULTS: The GST-pi expression rate was 69.6% in gastric mucosa with IM, significantly higher than that in gastric cancer (44.4%, P < 0.05) and that in normal gastric mucosa (0%, P <0.01). The GST-pi expression rate in IM II, IM III, and IM I decreased in sequence (83.3%, 71.1%, and 48.9%). The GST-pi expression rate in IM without H.pylori infection was 79.0%, significantly higher than that in IM with HP infection (64.2%, P <0.05). The positive rate of GST-pi expression in H.pylori eradicated group was 81.9%, significantly higher than that before H.pylori eradication (63.8%, P < 0.01). The GST-pi expression rate decreased from normal gastric mucous to IM and to gastric cancer, and from IM I -->II-->III too. CONCLUSION: IM III with low or no expression of GST-pi is a high-risk condition of gastric cancer. The risk of gastric cancer increases when low or no expression of GST-pi is combined with H.pylori infection. The carcinogen detoxification role of GST-pi and the virulence of H.pylori might interact each other in the stage of intestinal metaplasia, the precancerous condition of gastric cancer.
A key issue in the nucleotide excision repair (NER) of bulky carcinogen-DNA adducts is the ability of the NER machinery to recognize and repair certain adducts while failing to repair others. Unrepaired adducts can survive to cause mutations that initiate the carcinogenic process. Benzo[c]phenanthrene (B[c]Ph), a representative fjord region polycyclic aromatic hydrocarbon, can be metabolically activated to the enantiomeric benzo[c]phenanthrene diol epoxides (B[c]PhDEs), (+)-(1S,2R,3R,4S)-3,4- dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene and the corresponding (-)-(1R,2S,3S,4R) isomer. These react predominantly with adenine residues in DNA to produce the stereoisomeric 1R (+)- and 1S (-)-trans-anti-B[c]Ph-N6-dA adducts. Duplexes containing the 1R (+) or 1S (-) B[c]Ph-dA adduct in codon 61 of the human N-ras mutational hotspot sequence CA*A, with B[c]Ph modification at A*, are not repaired by the human NER system. However, the analogous stereoisomeric DNA adducts of the bay region benzo[a]pyrene diol epoxide (B[a]PDE), 10S (+)- and 10R (-)-trans-anti-B[a]P-N6-dA, are repaired in the same base sequence. In order to elucidate structural and thermodynamic origins of this phenomenon, we have carried out a 2 ns molecular dynamics simulation for the 1R (+)- and 1S (-)-trans-anti-B[c]Ph-N6-dA adducts in an 11mer duplex containing the human N-ras codon 61 sequence, and compared these results with our previous study of the B[a]P-dA adducts in the same sequence. The molecular mechanics Poisson- Boltzmann surface area (MM-PBSA) method was applied to calculate the free energies of the pair of stereoisomeric B[c]Ph-dA adducts, and a detailed structural analysis was carried out. The different repair susceptibilities of the B[a]P-dA adducts and the B[c]Ph-dA adducts can be attributed to different degrees of distortion, stemming from combined effects of differences in the quality of Watson-Crick hydrogen bonding, unwinding, stretching and helix backbone perturbations. These differences are due to the different intrinsic topologies of the rigid, planar bay region adducts versus the twisted, sterically hindered fjord region adducts.
The aim of the present paper is to review and evaluate, in a comprehensive manner, the most recent published evidence on the contribution of genetic susceptibility to gastric cancer risk in humans. We have identified all studies available in MEDLINE published up to October 2001. Only studies carried out in humans and comparing gastric cancer cases with at least 1 standard control group were included in the analysis. We were able to find 31 articles based on 25 case-control studies carried out in Caucasian, Asian and African populations. Most of the studies assess the effect of genes involved in detoxifying pathways (n = 12) and inflammatory responses (n = 7). The most widely studied is the GSTM1 null polymorphism. Only a very few studies have evaluated the risk of gastric cancer associated with genes acting on mucosa protection, oxidative damage and DNA repair. The most consistent results are the increased gastric cancer risk associated with IL1B and NAT1 variants, which may account for up to 48% of attributable risk of gastric cancer. Only polymorphisms at HLA-DQ, TNF and CYP2E genes may confer some protective effect against gastric cancer. The most important limitations that preclude definitive conclusions are (i) the lack of appropriate control of potential sources of bias (only 5 population-based studies have been published so far); (ii) the low number of cases analyzed (14 studies included fewer than 99 cases); and (iii) the low number of studies (n = 3) offering concomitant analysis of genetic susceptibility and exposure to relevant cofactors (Helicobacter pylori infection, diet and smoking). We conclude that the scientific data on the role of genetic factors in gastric cancer risk are promising. The lack of association reported so far should be considered with caution due to significant limitations in study design. Cohort studies taking into account simultaneously the different genetic and environmental factors potentially involved in gastric tumorigenesis are needed to ascertain not only the relative contribution of these factors to tumor development but also the contribution of their putative interactions.