OBJECTIVE: Association of glutathione-S-transferase M1 (GSTM1) polymorphisms and cancer has been demonstrated. Possible underlying mechanisms and genotype-phenotype correlations are not adequately investigated. The aim of this study was to investigate the influence of the GSTM1-null-genotype on the level of GSTM enzyme concentration and on the enzyme activity of GST in patients with head and neck cancer (HNC).
METHODS: We investigated in 83 patients and 91 healthy controls the GSTM1 polymorphisms, GSTM1 protein concentration, GSTM1 protein in tumor tissues, and total GST enzyme activity.
RESULTS: Total GST enzyme activity was significantly lower in patients with HNC (208 ± 9 μmol/min1) than in controls (264 ± 11 μmol/min1, P < 0.0001) but did not depend on GSTM1-genotype (P = 0.1). GSTM protein concentration in null-genotype patients (3.6 ± 2.5 μg/mL, mean ± SE) was significantly lower than in GSTM1 allele carriers (26.7 ± 9.6 μg/ml, P < 0.0001); GSTM protein expression did not depend on GSTM1-genotype (P > 0.5).
CONCLUSION: GST enzyme activity in patients with HNC is suppressed, indicating impaired detoxification capacity of tobacco-smoke-related carcinogens. This suppression is not correlated with the GSTM1-genotype. (Otolaryngol Head Neck Surg 2004;130:718-25.)
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References
1.
PabstMJHabigWHJakobyWBMercapturic acid formation: The several glutathione transferases of rat liver. Biochem Biophys Res Commun1973;52(4): 1123–8.
2.
PinkusLMKetleyJNJakobyWBThe glutathione S-transferases as a possible detoxification system of rat intestinal epithelium. Biochem Pharmacol1977;26(24): 2359–63.
3.
ChasseaudLFThe role of glutathione and glutathione S-transferases in the metabolism of chemical carcinogens and other electrophilic agents. Adv Cancer Res1979;29:175–274.
4.
HayesJDPulfordDJThe glutathione S-transferase supergene family: Regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol1995;30(6):445–600.
5.
InskipAElexperu CamiruagaJBuxtonNIdentification of polymorphism at the glutathione S-transferase, GSTM3 locus: Evidence for linkage with GSTM1A. Biochem J1995;312(Pt 3):713–6.
6.
PearsonWRVorachekWRXuSJIdentification of class-mu glutathione transferase genes GSTM1-GSTM5 on human chromosome 1p13. Am J Hum Genet1993;53(1):220–33.
7.
TuCPWeissMJLiNQReddyCCTissue-specific expression of the rat glutathione S-transferases. J Biol Chem1983;258(8):4659–62.
8.
MatthiasCBockmuhlUJahnkeVThe glutathione S-transferase GSTP1 polymorphism: Effects on susceptibility to oral/pharyngeal and laryngeal carcinomas. Pharmacogenetics1998;8(1):1–6.
9.
MatthiasCJahnkeVHandPImmunhistologische und Molekular genetische Untersuchungen des Effektes der Glutathion-S-transferase auf die Entstehung von Plattenepithelkarzinomen der Kopf-Hals-Region [Immunohistologic and molecular genetic studies of the effect of glutathione-S-transferases on the development of squamous epithelial carcinomas in the area of the head-neck]. Laryngorhinootologie1999;78:182–8.
10.
TsuchidaS.Purification and characterization of glutathione transferases with an activity toward nitroglycerin from human aorta and heart: Multiplicity of the human class mu forms. J Biol Chem1990;265(13):7150–7.
11.
SeidegardJPeroRWMillerDGA glutathione transferase in human leukocytes as a marker for the susceptibility to lung cancer. Carcinogenesis1986;7(5): 751–3.
12.
SeidegardJVorachekWRPeroRWHereditary differences in the expression of the human glutathione transferase active on trans-stilbene oxide are due to a gene deletion. Proc Natl Acad Sci USA1988;85(19): 7293–7.
SmithGStanleyLASimEMetabolic polymorphisms and cancer susceptibility. Cancer Surv1995;25:27–65.
15.
JahnkeVStrangeRMatthiasCGlutathione S-transferase and cytochrome P450 genotypes as risk factors for laryngeal carcinoma. Eur Arch Otorhinolaryngol Suppl1997;1:S147–9.
16.
HayashiSWatanabeJNakachiKGenetic linkage of lung cancer-associated MspI polymorphisms with amino acid replacement in the heme binding region of the human cytochrome P450IA1 gene. J Biochem Tokyo1991;110(3):407–11.
17.
KawajiriKNakachiKImaiKThe CYP1A1 gene and cancer susceptibility. Crit Rev Oncol Hematol1993;14(1):77–87.
18.
BrockmollerJKerbRDrakoulisNGlutathione S-transferase M1 and its variants A and B as host factors of bladder cancer susceptibility: A case-control study. Cancer Res1994;54(15):4103–11.
19.
LafuenteAPujolFCarreteroPHuman glutathione S-transferase mu (GST mu) deficiency as a marker for the susceptibility to bladder and larynx cancer among smokers. Cancer Lett1993;68(1):49–54.
20.
KiharaMNodaK.Risk of smoking for squamous and small cell carcinomas of the lung modulated by combinations of CYP1A1 and GSTM1 gene polymorphisms in a Japanese population. Carcinogenesis1995;16(1):2331–6.
21.
FordJGLiYO'SullivanMMGlutathione S-transferase M1 polymorphism and lung cancer risk in African-Americans. Carcinogenesis2000;21(11):1971–5.
22.
SeidegardJPeroRWMarkowitzMMIsoenzyme(s) of glutathione transferase (class mu) as a marker for the susceptibility to lung cancer: A follow-up study. Carcinogenesis1990;11(1):33–6.
23.
LafuenteAMolinaRPalouJPhenotype of glutathione S-transferase mu (GSTM1) and susceptibility to malignant melanoma: MMM (multidisciplinary malignant melanoma) group. Br J Cancer1995;72(2):324–6.
24.
ChenSXueKXuLPolymorphisms of the CYP1A1 and GSTM1 genes in relation to individual susceptibility to lung carcinoma in Chinese population. Mutat Res2001;458(1–2):41–7.
25.
GronauSKonig GregerDRettingerGGSTM1 Gen-Polymorphismen bei Patienten mit Kopf-Hals-Tumoren [GSTM1 gene polymorphism in patients with head and neck tumors]. Laryngorhinootologie2000;79:341–4.
26.
BaxterSWThomasEJCampbellIGGSTM1 null polymorphism and susceptibility to endometriosis and ovarian cancer. Carcinogenesis2001;22(1):63–5.
27.
D'ErricoAMalatsNVineisPReview of studies of selected metabolic polymorphisms and cancer. IARC Sci Publ1999;148:323–93.
28.
BrockmollerJKerbRDrakoulisNGenotype and phenotype of glutathione S-transferase class mu isoenzymes mu and psi in lung cancer patients and controls. Cancer Res1993;53(5):1004–11.
29.
DietzMIhrigABaderM. Einsatz des Arbeits-medizinisch-Neurotoxischen Evaluierungs-Systems zu Früherkennung Lösungsmittel asoziierter Effekte im Rahmen einer Längsschnittstudie. Arbeitsmedzin, Sozialmedizin, Umweltmedizin1999;34(5):185–93 [Neurotoxic evaluation system for early diagnosis of solvent-associated effects in occupational medicine] [ANES].
30.
HarveyJWBeutlerE.Binding of heme by glutathione S-transferase: A possible role of the erythrocyte enzyme. Blood1982;60(5):1227–30.
31.
HabigWHPabstMJJakobyWBGlutathione S-transferases: The first enzymatic step in mercapturic acid formation. J Biol Chem1974;249(22):7130–9.
32.
ComstockKEWiderstenMHaoXYA comparison of the enzymatic and physicochemical properties of human glutathione transferase M4-4 and three other human Mu class enzymes. Arch Biochem Biophys1994;311(2):487–95.
33.
HusseyAJHayesJDHuman Mu-class glutathione S-transferases present in liver, skeletal muscle and testicular tissue. Biochim Biophys Acta1993;1203(1):131–41.
34.
StrangeRCFryerAAChapter 19. The glutathione S-transferases: Influence of polymorphism on cancer susceptibility. IARC Sci Publ1999(148):231–49.
35.
XuSWangYRoeBCharacterization of the human class mu glutathione S-transferase gene cluster and the GSTM1 deletion. J Biol Chem1998;273(6): 3517–27.
