Autistic disorder: a review for the pediatric dentist

A combined analysis of two polymorphic enzymes, glutathione S-transferase mu (GST M1) and q (GST T1) and their implication as cancer risk factors was performed in a case-control study of lung and bladder cancers. Using a multiplex polymerase chain reaction (PCR) based method, the frequency of the homozygous deleted GSTM1 and GSTT1 genotypes was examined in 117 lung cancer patients, 67 urinary bladder cancer patients, and in a community-based sample of 248 healthy, unrelated individuals. In both cancer groups the frequency of the GSTM1 null genotype was higher in comparison with that of the control group (59% and 59.7% vs. 49.6%), but this increase did not reach statistical significance (p > 0.05). After grouping by the smoking status, among smokers in both cancer groups (62.1% in lung cancer and 71.4% in the bladder cancer group, respectively) there were statistically significantly (p < 0.05) increased frequencies of the GSTM1 deletion genotype as compared to the control group (49.6%). Smokers with absence of the GSTM1 gene were at an approximately 1.7-fold higher risk for lung cancer (odds ratio--OR = 1.67, 95% confidence interval--CI 95% = 1.0-2.7, p = 0.04) and an approximately 2.5-fold higher risk for bladder cancer (OR = 2.54, CI 95% = 1.2-5.5, p = 0.02). As related to GSTT1, our study demonstrated an overall GSTT1 effect on bladder cancer risk. Individuals with absence of the GSTT1 gene were at an approximately 2.5-fold higher risk of developing bladder cancer. In the lung cancer cases, the frequency of the putatively high risk GSTT1 null genotype was not increased as compared with controls. No effect of smoking was found on risk of lung and bladder cancer associated with the GSTT1 0/0 genotype. In combined analysis, the obtained results suggested that individuals who were both GSTM1 null and GSTT1 null may be at increased risk because they lack both enzymes. The findings suggest that the GSTM1 null genotype may be associated with susceptibility to lung and urinary bladder cancer in dependence on the exposure to carcinogens in cigarette smoke and that the GSTT1 null genotype is not a critical factor in mediating the risk of lung cancer, but may be associated with an increased susceptibility to bladder cancer.     

Higher frequency of glutathione S-transferase deletions in black children with acute lymphoblastic leukemia

The genetic polymorphisms in human glutathione S-transferases (GST) M1 and T1 have been associated with race, disease risk, and outcome of some adult cancers. Also, there are racial differences in the incidence and characteristics of childhood acute lymphoblastic leukemia (ALL). Our objectives were to compare the frequency of the null genotype for GSTM1, GSTT1, or both in children with ALL to that in healthy controls, and to determine whether GST genotype was associated with treatment outcome and prognostic factors. We studied GSTM1 and GSTT1 genotypes in somatic cell DNA from black children and white children with ALL and in 416 healthy controls, using a polymerase chain reaction technique. Ninety of 163 (55.2%) white ALL patients and 14 of 34 (41.2%) black patients were GSTM1 null, frequencies not significantly different (P = .19) than healthy controls (53.5% in whites and 27.6% in blacks), although there was a trend toward more null genotypes in black ALL patients. Twenty-three of 163 (14.1%) white ALL patients and 12 of 34 (35.3%) black ALL patients were GSTT1 null, not different (P = .34) than the frequencies in healthy controls (15.0% in whites and 24.1% in blacks). However, the frequency of the "double-null" genotype, lacking both GSTM1 and GSTT1, was higher in black patients with ALL (8 of 34 or 23.5%) than in black controls (3.9%) (P = .0005), but this was not the case in white patients with ALL (10 of 163 or 6.1%) compared to white controls (8.0%) (P = .68). In stratified analyses, the GST double-null genotype was not associated with other characteristics that might differ between whites and blacks with ALL, such as age, T-lineage immunophenotype, presenting white blood cell count, DNA index, or insurance status. The null genotype for GSTM1, GSTT1, or both was not found to be a prognostic factor for disease-free survival or probability of hematologic remission; central nervous system relapse tended to be less common in those with the GSTM1 null genotype (P = .054). The double-null genotype for GSTM1 and GSTT1 is more common among blacks but not whites with childhood ALL. These data suggest that GST genotype, coupled with unidentified additional risk factors, may play a role in risk of childhood ALL in American blacks.     

Glutathione S-transferase mu1 and N-acetyltransferase 2 genetic polymorphisms and exposure to tobacco smoke in nonsmoking and smoking lung cancer patients and population controls

We conducted a case-control study to assess the risk of lung cancer in relation to genetic polymorphisms of the detoxifying enzymes glutathione-S-transferase mu1 (GSTM1) and N-acetyl transferase 2 (NAT2), focusing on never-smokers, women, and older people. The study base consisted of persons > or =30 years of age in Stockholm County from 1992 to 1995. We recruited never-smoking lung cancer cases and a sex- and age-matched sample of ever-smoking cases at the three county hospitals mainly responsible for diagnosing and treating lung cancer. A total of 185 cases (25.4% men; 47.6% never-smokers) and 164 frequency-matched population controls (28.7% men; 48.2% never-smokers) supplied blood for genotyping. Detailed information was collected by interview on active and passive smoking, occupations, residences, and diet. The overall odds ratio (OR) for lung cancer associated with the GSTM1 null (GSTM1-) versus GSTM1+ genotype was 0.8 [95% confidence interval (CI), 0.5-1.2], with an OR close to unity among smokers, and lower ORs suggested among never-smokers. For NAT2 slow versus rapid acetylator genotypes, the OR was 1.0 (95% CI, 0.6-1.5) overall, which broke down into an increased risk for slow acetylators among never-smokers but an increased risk for rapid acetylators among smokers. Among never-smokers, a gene interaction was suggested, with combined slow acetylator and GSTM1+ genotype conferring particularly high risk (OR = 3.1; 95% CI, 1.1-8.6), but no clear pattern emerged among smokers. A detailed analysis among smokers showed no interaction between pack-years of smoking and the GSTM1 genotype but suggested a steeper increase in risk with increasing pack-years of smoking exposure for rapid than for slow acetylators. Our results do not support a major role for the GSTM1 genetic polymorphism as a risk factor for lung cancer among smokers or nonsmokers. There was, however, some suggestion that the slow acetylator genotype may confer an increased risk among never-smokers and that the rapid acetylator genotype interacts with pack-year dose to produce a steeper risk gradient among smokers.     

An association between the allele coding for a low activity variant of catechol-O-methyltransferase and the risk for breast cancer

Mounting evidence suggests that catechol metabolites of estradiol may contribute to the development of estrogen-induced cancers. O-Methylation, catalyzed by catechol-O-methyltransferase (COMT), inactivates catechol estrogens. COMT is polymorphic in the human population, with 25% of Caucasians being homozygous for a low activity allele of the enzyme (COMT(LL)). We hypothesized that low activity COMT may be a risk factor for human breast cancer and designed a PCR-based RFLP assay to determine COMT genotype in a cohort of 112 matched, nested case-control samples. In the total study population, the odds ratios for the association of breast cancer risk with COMT(HL) and COMT(LL) genotypes were 1.30 [confidence interval (CI), 0.66-2.58] and 1.45 (CI, 0.69-3.07), respectively. Postmenopausal COMT(LL) women had a greater than 2-fold increased risk of developing breast cancer [odds ratio (OR), 2.18; CI, 0.93-5.11]. The association of COMT(LL) with the development of postmenopausal breast cancer was stronger and statistically significant in those women with a body mass index >24.47 kg/m2 (OR, 3.58; CI, 1.07-11.98). When COMT(LL) was combined with either glutathione S-transferase (GST) M1 null or with GSTP1 Ile-105-Val/Val-105-Val (intermediate/low activity, respectively) genotypes, the risk for developing postmenopausal breast cancer was also significantly increased. Our findings suggest that the allele encoding low activity COMT may be an important contributor to the postmenopausal development of breast cancer in certain women.     

Influence of hyperthyroidism on the activity of liver nitric oxide synthase in the rat

Previous studies of associations of metabolic polymorphisms with the occurrence of malignant brain tumors have suggested that there is a significantly increased risk of development of adult gliomas in individuals who carry a poor metabolizer CYP2D6 variant allele and the GSTT1 null genotype. To investigate this further, a population-based case control study of adult glioma in the San Francisco Bay area was conducted. Patients (n = 188) diagnosed with brain tumors and controls (n = 166) were enrolled using random digit dialing and were frequency matched for age, ethnicity and gender. Genotyping for the polymorphisms was performed using standard PCR-based techniques. The analysis of the data was restricted to Caucasians because the prevalence of these traits is known to vary by ethnicity. No overall association of either the GSTT1 null genotype or CYP2D6 homozygous variant PM genotype was observed with the occurrence of brain tumors. However, when stratified by histopathologic subtype, there was a significantly increased risk for oligodendroglioma associated with the GSTT1 null genotype, with an OR of 3.2 (95% CI 1.1-9.2). These data suggest that the GSTT1 polymorphism may play a role in the development of a subset of malignant brain tumors in adults, and indicate the need for further studies.     

The outcome of contact tracing for gonorrhoea in the United Kingdom

BACKGROUND: The p53 mutation spectrum of prostate cancers developing in Japan indicates a role for environmental factors. This suggests there might be differences in susceptibility due to genetic polymorphisms in metabolic activation enzyme genes. We analyzed genetic polymorphisms of the xenobiotic-metabolizing enzymes, CYP1A1 and GSTM1. METHOD: Genotyping of CYP1A1 and GSTM1 was investigated by using allele-specific PCR in 115 prostate cancer (PCa) patients and 204 control patients. RESULTS: The CYP1A1 Val/Val genotype significantly increased the risk for PCa (OR = 2.6; 95% CI = 1.11-6.25) and the Ile/Val genotype showed a similar tendency (OR = 1.4; CI = 0.86-2.29). Individuals with the GSTM1 (0/0) genotype demonstrated a slightly increased risk (OR = 1.3; CI = 0.82-2.04). The combination of the CYP1A1 Val allele and GSTM1 (0/0) genotype was associated with a higher risk (OR = 2.3; CI = 1.18-4.48) than the CYP1A1 Val allele alone. When cases were analyzed by age at initial diagnosis, the relative risks with both the CYP1A1 Val allele and the GSTM1 (0/0) genotype were higher in the young group than in the old group (CYP1A1; OR = 1.7, CI = 0.89-3.17: GSTM1; OR = 1.6, CI = 0.84-2.99). The frequency of the GSTM1 (0/0) genotype was also higher in patients with advanced stage disease. In stage D, the OR was 1.7 with a CI of 0.93-3.17 and in stages A and B, the OR was 0.8 with a CI of 0.40-1.62. CONCLUSIONS: These results suggest that CYP1A1 and GSTM1 polymorphisms are linked to a propensity for PCa development.     

Glutathione S-transferase M1 and T1 and cytochrome P4501A1 polymorphisms in relation to the risk for benign and malignant head and neck lesions

BACKGROUND: Susceptibility to head and neck cancer in a particular individual may depend in part on the metabolic balance between Phase 1 enzymes, such as cytochromes P450 (CYPs), and Phase II enzymes, such as glutathione S-transferases (GSTs). Genetic variability in CYP and GST isoenzymes may contribute to individual differences in susceptibility to chemical carcinogenesis. GSTM1 and GSTT1 null genotypes as well as polymorphic variants in the CYP1A1 gene that may help determine the risk for head and neck cancer have been described in previous reports. METHODS: Polymorphisms of GSTM1, GSTT1, and CYP1A1 in whole blood were detected by polymerase chain reaction (PCR) in 185 patients with head and neck squamous cell carcinoma (HNSCC), 78 patients with benign head and neck lesions (BHNL), and 207 blood donors. RESULTS: GSTM1 null genotype was demonstrated to be equally frequent in patients with HNSCC (50.8%), patients with BHNL (47.4%), and blood donors (51.7%). GSTT1 null genotype occurred significantly more often in patients with BHNL (33.3%) as compared with blood donors (20.3%), demonstrating that lack of GSTT1 may be a risk factor for BHNL. Presence of the rare valine in the CYP1A1/Nco1 site was found in 33 patients with HNSCC (17.8%), in 20 patients with BHNL (25.6%), and in 34 blood donors (16.4%). The frequencies with which the presence of the rare cytosine nucleotide in the CYP1A1/Msp1 site was detected were 17.8%, 15.4%, and 15.9%, respectively. CONCLUSIONS: The occurrence of polymorphic variants in the GSTM1, GSTT1, and CYP1A1 genes did not differ between the groups investigated, therefore indicating no significant contribution to the development of head and neck cancer.     

Polymorphic expression of the glutathione S-transferase P1 gene and its susceptibility to Barrett's esophagus and esophageal carcinoma

Factors determining individual susceptibility to esophageal cancer or premalignant Barrett's epithelium are still largely unclear. An imbalance between phase I drug metabolism [e.g., cytochrome P450 (CYP)] and phase II detoxification [e.g., glutathione S-transferase (GST)] may contribute to the development of these diseases. Polymorphic variants in the CYP1A1 gene were described leading to increased levels of bioactive compounds, whereas polymorphisms in GST genes often resulted in impaired detoxification. We studied the frequencies of polymorphic variants in CYP1A1, GSTP1, GSTT1, and GSTM1 genes in 98 patients with Barrett's epithelium and 34 patients with esophageal cancer. The results were compared with those obtained from 247 healthy blood donors. DNA was extracted, and PCR-RFLP methods were used to detect genetic polymorphisms. Chi2 analysis, Spearman rank correlation, and Wilcoxon rank sum tests were used for statistical evaluation. Polymorphisms in CYP1A1, GSTM1, and GSTT1 occurred at an equal frequency in patients and controls. Occurrence of the polymorphic GSTP1b variant in the GSTP1 gene resulted in a significantly lower GST enzyme activity (P < 0.05), and GSTP1b was found significantly more often in patients with Barrett's epithelium (70%; P < 0.001) and patients with esophageal adenocarcinoma (76%; P = 0.005), as compared to healthy blood donors (41%). In conclusion, presence of the GSTP1b allele leads to lower GST enzyme activity levels and, consequently, impaired detoxification. This most important esophageal GST isoform may, therefore, contribute to the development of Barrett's epithelium and adenocarcinoma.     

Association of glutathione S-transferase GSTM1 and GSTT1 null genotypes with clinical outcome in epithelial ovarian cancer

Epithelial ovarian cancer is generally associated with a poor outcome, although the mechanisms that determine survival and progression-free interval (PFI) are unclear. Data from ovarian tumors showing associations between (a) null genotypes at the glutathione S-transferase GSTM1 and GSTT1 loci and expression of p53 protein and (b) outcome and expression of p53 suggest that polymorphism at these loci is a factor determining outcome. Accordingly, we have studied the association between the GSTM1 null and GSTT1 null genotypes and survival and PFI in 148 women with epithelial ovarian cancer. Although we did not find an association between individual genotypes and outcome, women with both GSTM1 null and GSTT1 null genotypes demonstrated poorer survival (P = 0.001) and reduced PFI (P = 0.003). Thus, no cases with both these genotypes survived past 42 months postdiagnosis. In contrast, 43% of the women without this combination survived beyond this time. Because response to chemotherapy is a major factor determining outcome in ovarian cancer, we also examined the data for associations between the glutathione S-transferase genotypes and response to such treatment. Thus, in 78 patients treated with chemotherapy, the combination of GSTM1 null and GSTT1 null was associated with unresponsiveness to primary chemotherapy (P = 0.004); none of the eight patients with both these genotypes responded, compared with 38 of 70 (54%) of patients with other genotype combinations. The effect of the combination of genotypes on survival and PFI was lost in a multivariate model that included response to chemotherapy as a confounding factor. This suggests that the combination of GSTM1 null/GSTT1 null is associated with outcome because of its influence on response to chemotherapy. These preliminary findings may provide a basis for the selection of patients for treatment with chemotherapeutic agents.     

Individual sensitivity to cytogenetic effects of 1,2:3,4-diepoxybutane in cultured human lymphocytes: influence of glutathione S-transferase M1, P1 and T1 genotypes

Although some blood parameters have been suggested to modulate in-vitro induction of sister chromatid exchanges by 1,2:3,4-diepoxybutane (DEB), a metabolite of 1,3-butadiene, the increased sensitivity has largely been assigned to a homozygous deletion of glutathione S-transferase T1 gene (GSTT1 null genotype). However, some DEB-sensitive individuals have been shown to be GSTT1 positive (having at least one undeleted GSTT1 allele). To examine potential causes for this overlap, we evaluated the effect of GSTM1, GSTP1, and GSTT1 genotypes, together with various life-style and blood parameters, on the DEB induction of sister chromatid exchanges and cells with chromosomal aberrations (aberrant cells) in lymphocyte cultures of 115 and 62 human donors, respectively. Our results supported the important role of the GSTT1 genotype in DEB sensitivity; 76% of cultures from GSTT1 null donors but only 4% of those from GSTT1 positive donors were DEB-sensitive, as defined by sister chromatid exchange measurements. The GSTT1 genotype also clearly affected DEB-induced aberrant cells, 92% of GSTT1 null and 8% of GSTT1 positive donors being sensitive to DEB. All individuals showing a high response to DEB in both sister chromatid exchange and aberrant cell analyses were GSTT1 null. Baseline aberrant cell measurements but not sister chromatid exchange measurements were marginally higher among GSTT1 null donors compared with GSTT1 positive donors. GSTM1 and GSTP1 genotypes had no influence on these cytogenetic end-points. Blood transaminases, gamma-glutamyl transferase, urea, creatinine and white blood cell count showed a clear negative association with DEB-induced aberrant cells, whereas wine drinkers had more aberrant cells than non-drinkers. A higher sister chromatid exchange-response to DEB was observed in lymphocytes from women and smokers than from men and non-smokers, respectively. Erythrocyte count correlated negatively with DEB-induced sister chromatid exchanges. Thus, a variety of parameters seemed to modulate the individual DEB-sensitivity together with the GSTT1 genotype. Although the known contributing factors accounted for a considerable part of individual variability in sister chromatid exchanges (59.4%) and aberrant cells (46.7%) in DEB treatment, they did not, however, fully explain the overlap in cytogenetic response between GSTT1 positive and null individuals.     

Biologic activity of interleukin 1 (IL-1) alpha in patients with refractory malignancies

To examine the effects of smoking and N-acetylation genetics on breast cancer risk, we analyzed data from an ongoing, population-based, case-control study of invasive breast cancer in North Carolina. The study population consisted of 498 cases and 473 controls, with approximately equal numbers of African-American and white women, and women under the age of 50 and age 50 years or older. Among premenopausal women, there was no association between current smoking [odds ratio (OR), 0.9; 95% confidence interval (CI), 0.5-1.5] or past smoking (OR, 1.0; 95% CI, 0.6-1.6) and breast cancer risk. Among postmenopausal women, there was also no association with current smoking (OR, 1.2; 95% CI, 0.7-2.0); however, a small increase in risk was observed for past smoking (OR, 1.5; 95% CI, 1.0-2.4). For postmenopausal women who smoked in the past, ORs and 95% CIs were 3.4 (1.4-8.1) for smoking within the past 3 years, 3.0 (1.3-6.7) for smoking 4-9 years ago, and 0.6 (0.3-1.4) for smoking 10-19 years ago. Neither N-acetyltransferase 1 (NAT1) nor N-acetyltransferase 2 (NAT2) genotype alone was associated with increased breast cancer risk. There was little evidence for modification of smoking effects according to genotype, except among postmenopausal women. Among postmenopausal women, ORs for smoking within the past 3 years were greater for women with the NAT1*10 genotype (OR, 9.0; 95% CI, 1.9-41.8) than NAT1-non*10 (OR, 2.5; 95% CI, 0.9-7.2) and greater for NAT2-rapid genotype (OR, 7.4; 95% CI, 1.6-32.6) than NAT2-slow (OR, 2.8; 95% CI, 0.4-8.0). Future studies of NAT genotypes and breast cancer should investigate the effects of environmental tobacco smoke, diet, and other exposures.     

Susceptibility to esophageal cancer and genetic polymorphisms in glutathione S-transferases T1, P1, and M1 and cytochrome P450 2E1

Genetic polymorphisms in enzymes involved in carcinogen metabolism have been shown to influence susceptibility to cancer. Cytochrome P450 2E1 (CYP2E1) is primarily responsible for the bioactivation of many low molecular weight carcinogens, including certain nitrosamines, whereas glutathione S-transferases (GSTs) are involved in detoxifying many other carcinogenic electrophiles. Esophageal cancer, which is prevalent in China, is hypothesized to be related to environmental nitrosamine exposure. Thus, we conducted a pilot case-control study to examine the association between CYP2E1, GSTM1, GSTT1, and GSTP1 genetic polymorphisms and esophageal cancer susceptibility. DNA samples were isolated from surgically removed esophageal tissues or scraped esophageal epithelium from cases with cancer (n = 45), cases with severe epithelial hyperplasia (n = 45), and normal controls (n = 46) from a high-risk area, Linxian County, China. RFLPs in the CYP2E1 and the GSTP1 genes were determined by PCR amplification followed by digestion with RsaI or DraI and Alw26I, respectively. Deletion of the GSTM1 and GSTT1 genes was examined by a multiplex PCR. The CYP2E1 polymorphism detected by RsaI was significantly different between controls (56%) and cases with cancer (20%) or severe epithelial hyperplasia (17%; P < 0.001). Persons without the RsaI variant alleles had more than a 4-6-fold risk of developing severe epithelial hyperplasia (adjusted odds ratio, 6.0; 95% confidence interval, 2.3-16.0) and cancer (adjusted odds ratio, 4.8; 95% confidence interval, 1.8-12.4). Polymorphisms in the GSTs were not associated with increased esophageal cancer risk. These results indicate that CYP2E1 may be a genetic susceptibility factor involved in the early events leading to the development of esophageal cancer.     

Parkinson's disease, pesticides, and glutathione transferase polymorphisms

BACKGROUND: Parkinson's disease is thought to be secondary to the presence of neurotoxins, and pesticides have been implicated as possible causative agents. Glutathione transferases (GST) metabolise xenobiotics, including pesticides. Therefore, we investigated the role of GST polymorphisms in the pathogenesis of idiopathic Parkinson's disease. METHODS: We genotyped by PCR polymorphisms in four GST classes (GSTM1, GSTT1, GSTP1, and GSTZ1) in 95 Parkinson's disease patients and 95 controls. We asked all patients for information about pesticide exposure. FINDINGS: The distribution of the GSTP1 genotypes differed significantly between patients and controls who had been exposed to pesticides (controls vs patients: AA 14 [54%] of 26 vs seven [18%] of 39; AB 11 [42%] of 26 vs 22 [56%] of 39; BB 1 [4%] of 26 vs six [15%] of 39; AC 0 vs four [10%] of 39, p=0.009). No association was found with any of the other GST polymorphisms. Pesticide exposure and a positive family history were risk factors for Parkinson's disease. INTERPRETATION: GSTP1-1, which is expressed in the blood-brain barrier, may influence response to neurotoxins and explain the susceptibility of some people to the parkinsonism-inducing effects of pesticides.     

Genetic polymorphisms in carcinogen metabolism and their association to hereditary nonpolyposis colon cancer

BACKGROUND & AIMS: The phenotype of hereditary nonpolyposis colorectal cancer shows interfamilial and intrafamilial variation even in the presence of identical predisposing mutations, suggesting the existence of additional phenotype determinants. The modifying role of genetic polymorphisms in loci involved in carcinogen metabolism was studied. METHODS: We focused on colon cancers from kindreds sharing one of two predisposing mutations (mutation 1 or 2) in the mismatch repair gene MLH1 (78 and 14 tumors, respectively). Polymorphisms in N-acetyltransferase 1 (NAT1) and glutathione S-transferase (GST) M1 and GSTT1 were investigated. RESULTS: The NAT1 allele 10 was associated with lower median age at diagnosis in both groups. In mutation 1 group, the NAT1 allele 10 was a risk factor for distal tumor location, both alone (P = 0.028) and combined with the GSTT1-positive genotype (P = 0.008). On the other hand, the combined null genotype of GSTM1 and GSTT1 was associated with proximal tumors. Associations with tumor location were not observed in patients with mutation 2, probably reflecting a small sample size. CONCLUSIONS: The results suggest that genetic polymorphisms in carcinogen metabolism modify the age of onset and tumor location in individuals with inherited deficiency of DNA mismatch repair.     

Urinary total isothiocyanate (ITC) in a population-based sample of middle-aged and older Chinese in Singapore: relationship with dietary total ITC and glutathione S-transferase M1/T1/P1 genotypes

Isothiocyanates (ITCs), degradation products of glucosinolates (which occur naturally in a variety of cruciferous vegetables), have been shown to exhibit chemopreventive activity. These compounds are metabolized in vivo to form the corresponding dithiocarbamates, which are the major urinary metabolites of ITCs, by a pathway involving the glutathione S-transferase (GST) class of enzymes. Using a newly developed assay that measures total ITC (primarily ITC conjugates) in urine, we examined the relationships between cruciferous vegetable intake (obtained from a food frequency/portion size questionnaire administered in person); dietary total ITC level; GSTM1, GSTT1, and GSTP1 genotypes; and levels of total ITC in spot urine samples collected from 246 Singapore Chinese (111 men and 135 women), ages 45-74 years, who are participants of the Singapore Cohort Study on diet and cancer. Consumption level of cruciferous vegetables was high in study subjects (mean consumption = 345 times per year, mean daily intake = 40.6 g), which was >3 times the comparable level of intake in the United States. Mean daily intake of total ITC among study subjects was 9.1 micromol, and there was a 2.5-fold difference between the 25th and 75th percentile values. Seventy-three % of study subjects tested positive for ITC in urine, and there was a 4-fold difference between the 25th and 75th percentile values among the positive subjects. There was a highly significant positive association between dietary intake and urinary excretion levels of total ITC (two-sided P = 0.0003) that was stronger than the association between overall cruciferous vegetable intake and urinary ITC level, which also was statistically significant (P = 0.0004). There was no difference in urinary ITC levels between GSTM1-null and GSTM1-positive study subjects (P = 0.61) or between subjects with differing GSTP1 genotypes (P = 0.77), but urinary excretion of ITC was significantly higher among GSTT1-positive subjects, relative to GSTT1-null subjects (P = 0.006). The strength of the association between GSTT1 genotype and urinary total ITC level was highly dependent on the level of cruciferous vegetable consumption (or dietary ITC level) in study subjects. Among subjects in the lowest tertile of cruciferous vegetable intake, there was little evidence of an association between GSTT1 genotype and urinary total ITC level (P = 0.67). In contrast, there was a strong and statistically significant association between GSTT1 genotype and urinary total ITC among subjects in the highest tertile of cruciferous vegetable intake (P = 0.02), whereas those in the middle tertile of cruciferous vegetable consumption exhibited an association of intermediate strength (P = 0.04). These results suggest the presence of GSTT1 inducers in cruciferous vegetables.     

Control of biologic hazards

Spontaneous and diepoxybutane (DEB)-induced sister-chromatid exchanges (SCEs) were examined in whole-blood lymphocyte cultures of 3 men and 4 women. A strong increase in mean number of SCEs per cell with increasing DEB concentrations (0, 2, and 4 microM) was observed in cultures of all subjects, but 3 of the donors were clearly more sensitive than the others. The SCE measurements were repeated 2-6 times per donor over a period of 55 months to assess the stability of the individual SCE response. The results showed that SCE induction by DEB was steady in the individuals during the follow-up at each DEB dose, with no significant differences among the repeated experiments. At 4 microM DEB, the DEB-sensitive and -resistant donors could be reliably be differentiated from each other in all trials. As DEB-sensitivity has been suggested to be due to the lack of glutathione S-transferase (GST) T1, the donors were genotyped for the presence of GSTT1 and GSTM1 genes. The 3 individuals found to be DEB-sensitive were all of the GSTT1 null genotype, whereas the 4 DEB-resistant donors were GSTT1 positive, which supported the role of the GSTT1 gene in determining DEB-sensitivity. Three of the DEB-resistant and none of the DEB-sensitive had the GSTM1 null genotype. Thus, the lack of the GSTM1 gene was not associated with the DEB-sensitivity trait. In conclusion, the present findings show that individual SCE responses to treatment of cultured human lymphocytes with DEB can reliably be reproduced in repeated trials. The results confirm that the GSTT1 gene but not the GSTM1 gene is important in determining individual sensitivity to the in vitro genotoxicity of DEB.     

History of lactation and breast cancer risk

A self-administered questionnaire was completed by 1,018 women diagnosed with breast cancer during 1988-1989 identified through the British Columbia Cancer Registry and by 1,025 controls selected at random from the Provincial Voters List. Parous premenopausal women who had never nursed (odds ratio (OR) = 1.3, 95% confidence interval (CI) 0.9-2.0) or who had lactated for 1 month or less (OR = 1.8, 95% CI 1.3-2.5) had an increased risk of breast cancer adjusted for age and parity, compared with women who had breast-fed 2 months or longer. The risk was particularly elevated (OR = 3.0, 95% CI 1.6-5.4) among women who reported having tried to nurse, but who were unsuccessful. Among women who nursed for at least 2 months, there was an indication of decreasing risk with increasing duration of nursing. Among postmenopausal parous women, no relation between lactation history and breast cancer risk was evident.     

Cocaine and cocaethylene binding to human milk

The relationship between frequency of intake of different types of fat and breast cancer was investigated in a case-control study conducted in Montevideo, Uruguay, during the time period 1994-1996. Our study comprised 365 cases and 397 controls. A moderate and non-significant increase in risk of breast cancer, associated with total fat intake, was found. Saturated and monounsaturated fat intake were not associated to an increased risk of this malignancy, whereas polyunsaturated fat and linoleic acid were associated with a significantly reduced risk (OR 0.26, 95% CI 0.13-0.53). On the contrary, both alpha-linolenic acid and cholesterol intakes were associated with an increased risk of breast cancer (OR for the upper quartile of intake of alpha-linolenic acid 3.79, 95% CI 1.53-9.40). When alpha-linolenic was examined at different levels of intake, the OR's were significantly higher at low levels of linoleic acid intake (OR 7.5, 95% CI 1.9-28.8).     

Degradation and repair of elastic fibers in rat lung interstitial fibroblast cultures

The results from previous studies have provided evidence to support the hypothesised association between intrauterine oestrogen exposure and subsequent risk of breast cancer. Information has not been available to study this relationship for several perinatal factors thought to be related to pregnancy oestrogen levels. Data collected from the mothers of women in two population-based case-control studies of breast cancer in women under the age of 45 years (510 case mothers, 436 control mothers) who were diagnosed between 1983 and 1992 in three western Washington counties were used to investigate further the relationship between intrauterine oestrogen exposure and risk of breast cancer. A pregnancy weight gain of 25-34 pounds was associated with breast cancer risk (odds ratio [OR] = 1.5; 95% confidence interval [CI] 1.1, 2.0); however, women whose mothers gained 35 pounds or more were not at increased risk. Use of antiemetic medication in women with any nausea and vomiting (OR = 2.9; 95% CI 1.1, 8.1) and use of diethylstilboestrol (DES) (OR = 2.3; 95% CI 0.8, 6.4) appeared to be positively associated with breast cancer risk. The results from this study provide limited support for the hypothesis that in utero oestrogen exposure may be related to subsequent breast cancer risk among young women.     

The association of calcium and vitamin D, and colon and rectal cancer in Wisconsin women

BACKGROUND: Calcium and vitamin D have been hypothesized to reduce colorectal cancer risk. Epidemiological evidence, however, is mixed. METHODS: To explore those relationships, data were collected as part of a population-based, case-control study of colorectal cancer in Wisconsin women (678 controls, 348 colon and 164 rectal cancer cases). A semi-quantitative food frequency questionnaire was used to ascertain food and dietary supplement intake 2 years prior to interview. Logistic regression models were used to calculate odds ratios (OR). RESULTS: Higher levels of calcium intake were associated with reduced colon and rectal cancer risk. The following adjusted OR and 95% confidence intervals (CI) were observed, comparing the fifth quintile (based on control intake) with the first: colon cancer: OR = 0.6, 95% CI: 0.4-1.0, P-trend: 0.03; rectal cancer: OR = 0.6, 95% CI: 0.3-1.1, P-trend: 0.07. Similar relationships were observed for vitamin D intake, although OR were closer to the null value and did not always behave in a step-wise fashion (fifth quintile versus the first--colon cancer: OR = 0.7, 95% CI: 0.4-1.1, P-trend: 0.05; rectal cancer: OR = 0.8, 95% CI: 0.5-1.5, P-trend: 0.42). CONCLUSION: These data support a protective association of calcium on colon and rectal cancer risk.