ABSTRACT
AIM: The effect of GSTM1 and GSTT1 allelic polymorphisms was studied on the HPV-induced cervical carcinogenesis. PATIENTS AND METHODS: Two hundred and fifty-three women with persistent high-risk HPV infection were involved in the study; 117 of them developed cervical high-grade dysplasia and/or cervical intraepithelial neoplasia grade III during the 7-year follow-up period. Occurrence of GSTM1 and GSTT1 null genotypes was compared between women with and without dysplasia. RESULTS: Presence of GSTM1 (OR=1.78, 95% CI=1.06-2.97; p=0.028) and GSTT1 (OR=1.89, 95% CI=1.10-3.26; p=0.022) null genotypes was statistically significantly more frequent among women with cervical dysplasia than in the group without dysplasia. Participants with dual null genotype had an even more elevated risk of precancerous lesion (OR=2.35, 95% CI=1.17-4.73; p=0.017). CONCLUSION: Our study demonstrated the role of both GSTM1 and T1 null genotypes in the development of high-grade cervical dysplasia in a Caucasian population.
Subject(s)
Alleles , Alphapapillomavirus/pathogenicity , Glutathione Transferase/genetics , Isoenzymes/genetics , Polymorphism, Genetic , Uterine Cervical Dysplasia/genetics , Adult , Base Sequence , DNA Primers , Female , Humans , Middle Aged , Uterine Cervical Dysplasia/virologyABSTRACT
7,12-Dimethylbenz[a]anthracene (DMBA) and N-methyl-N-nitrosourea (MNU) are important environmental carcinogens. Their different biological effects were examined in CBA/Ca H-2(K) haplotype inbred mice on the gene expression of c-myc, Ha-ras and p53 through a 24 hour period. Elevated expression of c-myc and Ha-ras genes was found in the spleen, lung, thymus and lymph nodes 6 and 12 hours after DMBA treatment and in the lung and thymus 3 hours after MNU treatment. In the liver, DMBA induced strong onco/suppressor gene expression as early as 6 hours after the treatment, but MNU increased the p53 gene expression 12 hours after the treatment. The gene expression patterns reflected the different mechanism of the direct acting MNU and metabolically activated DMBA. This phenomenon provides evidence as to the usefulness of detection of onco/supressor key gene expression as early molecular epidemiological biomarkers of carcinogenesis and carcinogenic exposure in animal model, useful in human cancer prevention practice as well.
Subject(s)
9,10-Dimethyl-1,2-benzanthracene/toxicity , Carcinogens/toxicity , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Tumor Suppressor Protein p53/genetics , 9,10-Dimethyl-1,2-benzanthracene/chemistry , Alkylating Agents/chemistry , Alkylating Agents/toxicity , Animals , Carcinogens/chemistry , Female , Gene Expression Regulation, Neoplastic/drug effects , Male , Methylnitrosourea/chemistry , Methylnitrosourea/toxicity , Mice , Mice, Inbred CBAABSTRACT
Methylnitrosourea (MNU) is a well-known pluripotent direct-acting carcinogen. Formation of MNU following incubation of various meats with additional nitrite under in vitro acidic conditions is possible. It is possible that many species, including humans, are exposed to carcinogenic MNU, generated in their alimentary tract. Previously, an animal model was developed by our research group to investigate the expression of three genes c-myc, Ha-ras and p53 as early molecular epidemiological biomarkers of carcinogenic exposure or carcinogenesis caused by DMBA (dimethylbenz[alpha]anthracene). The aim of this study was to investigate the early effect of MNU on the gene expression levels. MNU is a direct-acting carcinogen which spontaneously and rapidly degrades, so any effect on the gene expression is observed in 24 hours. Our results show the maximum effect in vivo on the gene expression at 12 hours after the MNU treatment; on the other hand, 24 hours after the treatment, the elevated gene expressions decreased in target organs (bone marrow, lung, lymph nodes). Our results correspond to "long-term" experiments of the carcinogenic effect of MNU in different target organs. Our findings suggest that MNU has an impact on the expression of c-myc, Ha-ras and p53 genes in 12 hours, especially in bone marrow. Overexpression of these genes occurs as an early biological effect of exposure to chemical carcinogens. According to our results, the high expression of these genes could indicate MNU exposure and these genes could take part in MNU-induced tumorigenesis.
Subject(s)
Genes, myc/drug effects , Genes, p53/drug effects , Genes, ras/drug effects , Methylnitrosourea/pharmacology , Animals , Carcinogens/pharmacology , Female , Gene Expression Regulation/drug effects , Male , Mice , Mice, Inbred CBA , Organ Specificity , RNA, Messenger/drug effects , RNA, Messenger/geneticsABSTRACT
BACKGROUND: Genetic polymorphisms of metabolizing enzymes may affect the risk of cancer formation in humans. Since the diet can contain polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (HAs), the relationship between polymorphisms of enzymes involved in PAH and HA metabolism and the occurrence of sporadic colorectal cancer was studied. PATIENTS AND METHODS: Five hundred colorectal cancer patients and 500 controls were genotyped for cytochrome P450 enzymes (CYP) 1A1 Ile/Val, CYP 1A2*1F, CYP 2E1 c1/c2, microsomal epoxy hydrolase (mEH) exon 3 Tyr113His and exon 4 His139Arg polymorphisms by allele-specific polymerase chain reaction (PCR) or PCR-restriction fragment length polymorphism (RFLP). RESULTS: The presence of CYP 1A1 Val, CYP 2E1 c2 and mEH exon 3 His alleles was statistically significantly associated with the occurrence of colorectal cancer (OR: 1.44 95% CI: 1.04-2.00; OR: 1.74 95% CI: 1.15-2.65; OR: 1.79 95% CI: 1.10-2.92, respectively). CONCLUSION: These findings suggest that allelic polymorphism of metabolizing enzymes play an important role in human colorectal carcinogenesis by affecting the metabolism of dietary carcinogens.
