ABSTRACT
OBJECTIVE: Impaired detoxification of carcinogens found in tobacco smoke appears to increase the risk for tobacco associated cancer. The objective of this study was to investigate concomitant polymorphisms in genes encoding for various detoxification enzymes in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: In 187 patients with HNSCC and in 139 healthy control subjects, the polymorphisms of cytochrome P450 1A1 (CYP1A1), cytochrome P450 2D6 (CYP2D6), and glutathione S-transferase mu1 and Theta (GSTM1, GSTT1) were detected by polymerase chain reaction. RESULTS: No significant association were identified between CYP1A1 and CYP2D6 gene polymorphisms and HNSCC. Patients with laryngeal cancer revealed the GSTM1 null genotype more frequently than did the control subjects (P < 0.05). The coincidence of GSTM1 and GSTT1 null genotype was found twice as great in patients as in control subjects (P < 0.05). CONCLUSIONS: It is assumed that detoxification enzymes are functionally redundant and only the simultaneous deficiency of several detoxification enzymes increase the risk for HNSCC in alcohol- and tobacco-exposed individuals.
Subject(s)
Aryl Hydrocarbon Hydroxylases/genetics , Carcinoma, Squamous Cell/enzymology , Carcinoma, Squamous Cell/genetics , Glutathione Transferase/genetics , Head and Neck Neoplasms/enzymology , Head and Neck Neoplasms/genetics , Inactivation, Metabolic/genetics , Polymorphism, Genetic/physiology , Aged , Alcohol-Related Disorders/genetics , Alcohol-Related Disorders/metabolism , Aryl Hydrocarbon Hydroxylases/metabolism , Cytochrome P-450 CYP1A1/genetics , Cytochrome P-450 CYP1A1/metabolism , Cytochrome P-450 CYP2D6/genetics , Cytochrome P-450 CYP2D6/metabolism , Female , Genetic Predisposition to Disease/genetics , Genotype , Glutathione Transferase/metabolism , Humans , Inactivation, Metabolic/physiology , Male , Middle Aged , Tobacco Use Disorder/genetics , Tobacco Use Disorder/metabolismABSTRACT
BACKGROUND: Differences in genotype and phenotype of detoxification genes could be one reason for conflicting results in studies dealing with gene polymorphisms as susceptibility factors for tobacco associated cancer. OBJECTIVES: The objective of this study was to investigate gene polymorphisms of detoxification enzymes and to determine whether the enzyme concentration and activity of glutathione S transferase microliter 1 correlates with the genotype in patients with cancer of the oral cavity. MATERIAL AND METHODS: In 73 cancer patients and 136 matched healthy controls, the polymorphisms of glutathione S-transferase mu1 and theta (GSTM/GSTT), cytochrome p450 1A1 and CYP2D6 were detected. Simultaneously, GSTM1 protein concentration and total GSTM1-activity were determined. RESULTS: Only the coincidence of GSTM1 and GSTT null genotype was associated with oral cavity cancer. GSTM1 protein concentration and enzyme activity in null-genotype patients was significantly lower than in GSTM1-allele-carrier. But the enzyme concentration did not correlate with the activity. CONCLUSION: We assume that detoxification enzymes are functionally redundant and that only the simultaneous deficiency of several detoxification enzymes increases the risk for oral cancer.
Subject(s)
Carcinoma, Squamous Cell/enzymology , Glutathione Transferase/genetics , Glutathione Transferase/metabolism , Inactivation, Metabolic/genetics , Mouth Neoplasms/enzymology , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/genetics , Case-Control Studies , Cytochrome P-450 CYP1A1/genetics , Cytochrome P-450 CYP2D6/genetics , Female , Genetic Predisposition to Disease/genetics , Genotype , Glutathione Transferase/analysis , Humans , Male , Middle Aged , Mouth Neoplasms/genetics , Polymerase Chain Reaction , Polymorphism, Genetic , Statistics, NonparametricABSTRACT
11Beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) has been identified as a major detoxification enzyme of one of the most potent tobacco smoke-derived carcinogens, NNK. If not metabolized by 11beta-HSD1, activation of NNK by cytochrome p450 mono-oxidase 2D6 (CYP2D6) results in an electrophile intermediate responsible for DNA damage. Interindividual variability in the expression of 11beta-HSD1 and CYP2D6 has been found to influence the susceptibility to lung cancer. The aim of this study was to compare 11beta-HSD1 mRNA expression and CYP2D6 metabolizer status in pharyngeal tissues of patients with oropharyngeal carcinoma and controls. In 20 patients with oropharyngeal cancer and 15 non-smoking controls, the 11beta-HSD1 mRNA expression was assessed with RT-PCR. The frequency of genetic polymorphisms of the CYP2D6 gene was assessed using RFLP. It was found that 11beta-HSD1 mRNA is expressed in human pharyngeal mucosa. It is upregulated in mucosa exposed to tobacco smoke. In tumour tissues, 11beta-HSD1 expression was significantly lower than in non-affected mucosa. The frequency distribution of CYP2D6 gene polymorphisms was similar in patients and controls. Chronic tobacco abuse results in 11beta-HSD1 enzyme induction. A reduction of 11beta-HSD1 expression in tumour tissues could be a consequence of malignantly transformed cells. It remains unclear if the lower 11beta-HSD1 expression gives rise to an increased rate of additional mutations.
