S-transferase P1 Research Articles

Polymorphism of Glutathione S-Transferase M1 and P1 in Patients with Cystic Fibrosis and Chronic Respiratory Diseases

Polymorphism of GSTM1 and GSTP1 genes was studied in patients with cystic fibrosis (CF) and chronic bronchopulmonary diseases (CBPD) living in Bashkortostan. A combination of certain GSTM1 and GSTP1 genotypes accompanied by severe mutations in CFTR gene proved to intensify a pathologic process in respiratory organs of patients with CF; a combination of the normal GSTM1 and heterozygous I/V GSTP1 genotypes is the most favorable (OR = 4.49; chi 2 = 11.53, P < 0.002). In patients with CBPD, a combination of the GSTM1 null genotype and the homozygous GSTP1 V/V genotype is the most common (5.5% versus 1.3% in control; chi 2 = 3.01, P = 0.08). The frequency of this genotype is highest in groups of patients with recurrent bronchitis (8.1%; P = 0.07; OR = 6.75) and bronchiectatic disease (BED) (9.1%, P > 0.10, OR = 7.65). A combination of the null GSTM1 and I/V GSTP1 genotypes was found in 40.0% of patients with chronic nonobstructive bronchitis (chi 2 = 4.87; P = 0.03; OR = 4.03). Among patients with BED, a proportion of individuals with the normal GSTM1 and I/V GSTP1 genotypes was increased (36.4% versus 19.4% in control). In patients with chronic obstructive pulmonary disease (COPD), the frequencies of the GSTM1 and GSTP1 genotype combinations virtually did not differ from those in the control group suggesting that COPD severity is not related to changes in activities of glutathione S-transferases M1 and P1.

A cross-sectional study of polycyclic aromatic hydrocarbon-DNA adducts and polymorphism of glutathione S-transferases among heavy smokers by race/ethnicity

Differences in lung cancer risk by race/ethnicity have been observed among smokers. To determine whether these observations might reflect differences in the formation of carcinogen-DNA adducts, we analysed blood specimens (n =151) collected from smokers who were recruited for possible participation in an antioxidant vitamin intervention study. Mononuclear cells were analysed for polycyclic aromatic hydrocarbon (PAH)-DNA adducts by competitive enzyme-linked immunosorbent assay. Genotypes of glutathione S-transferase M1 and P1 (GSTM1 and GSTP1), enzymes involved in the detoxification of PAH metabolites, were determined by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism, respectively. GSTM1 was present in 65 out of 88 (73.4%), 16 out of 32 (50.0%) and 16 out of 29 (54.8%) of African-Americans, Caucasians and Latinos, respectively (p =0.022). Homozygosity for the GSTP1 codon 105 variant was found in 25.6%, 6.3% and 10.0% of African-Americans, Caucasians and Latinos, respectively (p =0.023). Regression analysis of the log-transformed adduct levels confirmed that Caucasian and Latino subjects had lower PAH-DNA adduct levels than African-American subjects, after adjustment for gender, education,α -tocopherol and β-carotene levels, and GSTM1 status. Further adjustment for age and current smoking habits had no impact on these findings. Although crude analysis suggested that the GSTM1-positive genotype may be associated with lower PAH-DNA levels in Caucasians (but not in African-Americans or Latinos), a formal test for interaction between GSTM1 and ethnicity was not significant. We found no association between adduct levels and GSTP1 genotype. Although the mechanism is unclear, ethnic differences in DNA damage levels may in part explain why African-Americans have higher lung cancer incidence rates than other ethnic groups.

Is there an influence of enzyme polymorphisms on ochratoxin A genotoxicity?

Primary cultured human urothelial cells derived from ureter specimens of urological patients were used to evaluate induction of DNA-damage by OTA in the alkaline single-cell gel electrophoresis (comet) assay. With the cultured cells from each donor a separate comet assay was performed and tail length of the damaged DNA was measured. A broad spectrum of effects was detected between the individual cell cultures with effects reaching from tail lengths on control level up to strongly enhanced tail lengths.All donors of urothelial tissue were additionally genotyped for several xenobiotic metabolising enzymes (cytochrome P450 1A2, glutathione S-transferases T1, M1, and P1, N-acetyltransferase 2) in lymphocyte DNA. The genotype was then correlated with the genotoxic effects obtained in the comet assay.No correlation was found with CYP1A2, GSTT1, and GSTM1 genotypes whereas for GSTP1 stronger genotoxic effects were found in cells from donors with hetero-and homozygously mutated (w/m, m/m) genotypes compared to homozygous wildtypes. The strongest hint for a correlation was found for NAT2, as cells from donors with homozygous mutated alleles (m/m), known as slow acetylators, displayed a higher susceptibility to OTA in the comet assay than cells from donors with the heterozygously mutated or wildtype alleles (rapid acetylators).

Chen and Chiou Respond to “Arsenic and Cancer of the Urinary Tract” by Cantor

Received for publication December 11, 2000, and accepted for publication December 19, 2000. Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan. Department of Public Health, College of Medicine, Taipei Medical University, Taipei, Taiwan. Reprint requests to Prof. Chien-Jen Chen, 1 Jen-Ai Road, Section 1, Taipei 10018, Taiwan (e-mail: cjchen@ha.mc.ntu.edu.tw). In his commentary (1) on our paper (2), Cantor has provided an excellent summary of the current state of knowledge on ingested arsenic and cancer risk. He has also highlighted a number of important issues regarding the epidemiologic study of risk of arsenic-induced cancers due to arsenic in drinking water. We shall briefly address several of his comments. As Cantor points out, there is an urgent need to reassess the maximum contamination level of arsenic in drinking water. Global environmental change, rapid population growth, and manmade pollution have led to a shortage of available surface water for drinking and cooking in many countries. In more and more areas, underground water is being used as the main source of water for daily consumption. Since arsenic is a ubiquitous element in the earth’s crust and is abundant in well water, arseniasis is becoming an emerging epidemic in several Asian countries (3). Epidemiologic studies on skin cancer carried out in southwestern Taiwan have long been used for risk assessment of arsenic in drinking water (4). Because the water of shallow wells in this arseniasis-endemic area had a high salt content, rather than microbial contamination as observed in Bangladesh and West Bengal, India, residents in the area had used high-arsenic artesian well water from the early 20th century to the 1970s. There was a striking difference in the arsenic levels of water obtained from shallow wells and artesian wells. Since vital statistics were collected at the village level and there were several wells in each village that were shared by villagers, the median arsenic level of water in the wells of a given village was used as the exposure information. In our earlier studies on arsenic and internal cancers (5, 6), we grouped arsenic levels in well water into three broad groups: <300, 300–599, and ≥600 μg/liter. In a reanalysis of cancer mortality using more refined exposure levels, we found that the current maximum contamination level of 50 μg/liter is associated with a substantial excess risk of cancer and is not sufficiently protective of public health (7, 8). However, the data from southwestern Taiwan had two limitations, as Cantor noted: 1) use of the median level of arsenic during the 1960s as the exposure dose and 2) use of mortality rather than incidence to estimate cancer risk. Our current study in northeastern Taiwan (2) provided better measurement of arsenic levels in individual households. Furthermore, we used incidence rather than mortality to assess the risk of transitional cell carcinoma. As Cantor mentioned, our conclusions were indeed based on the assumption that current or recent measures of arsenic in water from these wells could represent long term historical levels. We conducted retests of arsenic levels in the water of randomly sampled wells. The correlation for the repeated measurements was quite high. Although 2,199 (26 percent) of the study subjects had changed wells at some time prior to study enrollment, they had used their current wells for approximately 60 percent (standard deviation 21) of their life span. In other words, most of them had used their current wells for at least 10 years. There is indeed individual susceptibility to arsenic-induced health hazards. Undernourishment, liver dysfunction, poor arsenic methylation capability, and low serum levels of antioxidant vitamins have been found to increase the risk of arsenic-related vascular diseases and skin cancer (9–12). Genetic polymorphisms of glutathione S-transferases M1, T1, and P1 and several DNA repair enzymes were recently found to modify the risks of skin cancer and transitional cell carcinoma induced by arsenic (13–15). Both acquired and genetic susceptibility must be taken into consideration in assessment of the risk of arsenic. Inorganic arsenic is readily absorbed through ingestion and is widely distributed in the human body. It does not require metabolic activation to exert its effects. The health hazards of arsenic do not show any unique organotropism. In addition to various malignant neoplasms and circulatory diseases (16, 17), arsenic has been documented to induce diabetes mellitus and lens opacity (18, 19). Diseases other than cancer must be considered in setting the maximum contamination level of inorganic arsenic in drinking water.

Benzo(a)pyrene diolepoxide adducts to albumin in workers exposed to polycyclic aromatic hydrocarbons: association with specific CYP1A1, GSTM1, GSTP1 and EHPX genotypes

We investigated whether the presence of (+)-anti-benzo(a)pyrene diolepoxide adductsto serum albumin (BPDE-SA) among workers exposed to benzo(a)pyrene (BaP) and unexposed reference controls was influenced by genetic polymorphisms of cytochrome P4501A1 (CYP1A1), microsomal epoxide hydrolase (EHPX), glutathione S-transferases M1 (GSTM1) and P1 (GSTP1), all involved in BaP metabolism. Exposed workers hadsignificantly higher levels of adducts (0.124 ± 0.02 fmol BPTmg−1 SA, mean ± SE) and a higher proportion of detectable adducts (40.3%) than controls (0.051 ± 0.01 fmol BPT mg−1 SA; 16.1%) (p = 0:014 and p = 0:012). Smoking increased adduct levels only in occupationally exposed workers with the GSTM1 deletion (GSTM1 null) (p = 0:034).Smokers from the exposed group had higher adduct levels when they were CYP1A1 *1/*1 wild-type rather than heterozygous and homozygous for the variant alleles (CYP1A1 *1/*2 plus *2/*2) (p = 0:01). The dependence of BPDE-SA adduct levels and frequency on the CYP1A1 *1/*1 genotype was most pronounced in GSTM1-deficient smokers. Exposed workers with GSTM1 null/GSTP1 variant alleles had fewerdetectable adducts than those with the GSTM1 null/GSTP1*A wild-type allele, supporting for the first time the recent in vitro finding that GSTP1 variants may bemore effective in the detoxification of BPDE than the wild-type allele. Logistic regression analysis indicated that occupational exposure, wild-type CYP1A1*1/*1 allele and the combination of GSTM1 null genotype+EHPX genotypes associated with predicted low enzyme activity were significant predictors of BPDE-SA adducts. Though our findings should be viewed with caution because of the relatively limited size of the populationanalysed, the interaction between these polymorphic enzymes and BPDE-SA adducts seems to be specific for high exposure and might have an impact on the quantitative risk estimates for exposure to polycyclic aromatic hydrocarbons.

99/02797 Glutathione S-transferase M1 and P1 genotypes and urinary excretion of 1-hydroxypyrene in coke oven workers

99/02797 Glutathione S-transferase M1 and P1 genotypes and urinary excretion of 1-hydroxypyrene in coke oven workers