Dietary factors and epithelial cell exfoliation in the human colon.
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Cell Division↗
Biomedical subjects
A Loktionov
Publications and source records attributed to A Loktionov.
NQO1 and mEH exon 4 (mEH4) gene polymorphisms, smoking and colorectal cancer risk.
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Case-Control Studies↗
Glutathione-S-transferase gene polymorphisms in colorectal cancer patients: interaction between GSTM1 and GSTM3 allele variants as a risk-modulating factor.
The distribution of polymorphisms in the glutathione S-transferase (GST) family genes has been studied in 355 healthy controls and 206 cancer (59 proximal and 147 distal) patients. All controls were subjected to flexible sigmoidoscopy. Odds ratios (OR) after stratification by age, gender and smoking were slightly higher in the cancer group as a whole for GSTM1-null (*0/*0), GSTT1-null (*0/*0) and GSTM3 *A/*B or *B/*B when compared with the control group, but the differences did not reach statistical significance. GSTP1 variants had no effect. Separate analysis of patients with proximal and distal tumours has shown stronger associations for the distal cancers, the GSTM3*B allele presence being significantly more frequent in these patients [OR = 1.77; 95% confidence interval (CI) = 1.15-2.74]. Taking into account strong linkage between the GSTM1*A and GSTM3*B alleles, a separate analysis of the GSTM1-nulled individuals was undertaken. The combination of GSTM1-null genotype with GSTM3*B allele presence (*A/*B or *B/*B) was significantly overrepresented among patients with proximal and distal tumours taken together (OR = 2.12; 95% CI = 1.24-3.63), and especially in distal cancer patients (OR = 2.75; 95% CI = 1.56-4.84). Male individuals displayed a stronger association between the presence of the GSTM1-null in combination with GSTM3 *A/*B or *B/*B and distal tumours with a higher odds ratio (OR = 3.57; 95% CI = 1.73-7.36). In contrast, the frequency of GSTM1 *B/*0 or *B/*B combined with GSTM3 *A/*A was significantly lower in patients with distal colorectal cancer, especially in males (OR = 0.37; 95% CI = 0.15-0.92). Neither of these combinations was associated with proximal tumours. Our findings suggest that interactions of polymorphic genotypes within the GSTM gene cluster affect individual susceptibility to colorectal carcinogenesis, the GSTM3*B variant presence being a risk factor especially in combination with the GSTM1-null genotype.
Alleles↗
Gene-nutrient interactions: dietary behaviour associated with high coronary heart disease risk particularly affects serum LDL cholesterol in apolipoprotein E epsilon4-carrying free-living individuals.
Apolipoprotein E (ApoE) genotype influence on the relationship between dietary risk factors for cardiovascular disease and blood serum lipid levels was investigated in 132 free-living individuals participating in the European Prospective Investigation of Cancer (EPIC) study. All subjects (age 40-69) were clinically healthy and provided information on their usual diet. ApoE genotype and serum lipid concentrations were determined in all subjects. Relationships of intake of dietary constituents with serum lipid levels were compared in different genotype groups. There was a significant correlation between total serum cholesterol and intake of energy derived from total fat (r 0.195; P 0.025) and saturated fat (r 0.174; P 0.046) in the cohort as a whole. However, individuals with the ApoE epsilon3/epsilon4 genotype displayed a much stronger positive correlation between LDL cholesterol level and the percentage of energy derived from intake of saturated fat (r 0.436; P 0.043). There were no significant associations in the groups with epsilon3/epsilon3 or epsilon2/epsilon2 & epsilon2/epsilon3 genotype. A significant positive correlation between alcohol consumption and HDL cholesterol level was present in individuals bearing ApoE epsilon2 allele. These findings support current public health recommendations that saturated fat consumption should be reduced in order to reduce coronary heart disease risk. Total cholesterol concentrations were positively related to saturated fat intake in the cohort as a whole, but elevated LDL cholesterol levels associated with high saturated fat intake can be expected particularly in those individuals who combine a 'risky' dietary behaviour with the presence of the epsilon4 variant of ApoE.
Adult↗
Apolipoprotein E and methylenetetrahydrofolate reductase genetic polymorphisms in relation to other risk factors for cardiovascular disease in UK Caucasians and Black South Africans.
Genetic polymorphisms for apolipoprotein E (apo E) and methylenetetrahydrofolate reductase (MTHFR) are believed to modulate risk of coronary heart disease (CHD) acting through regulation of lipid and homocysteine metabolism, respectively. The distributions of apo E and MTHFR alleles in Black South Africans, a population with a low CHD incidence, and UK Caucasians from the Cambridge area, with a higher CHD incidence, were therefore compared. Clinically healthy volunteers (207), including 107 UK Caucasians from the Cambridge area and 100 Black South Africans, participated in the study. Apo E and MTHFR genotypes were determined in all of them. Analyses for serum total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides and plasma fibrinogen were carried out in 65 UK Caucasians and 60 Black South Africans. The apo E epsilon4 allele, which is associated with elevated CHD risk, was present in 48% of Black South Africans compared to 20.8% of Caucasians (P < 0.0001); however, both total and LDL cholesterol levels in Black South Africans were 18-32% lower than in Caucasians with similar apo E genotypes. Hyperhomocysteinemia-causing MTHFR 677T variant was detected in only 20% of Black South Africans (no homozygotes) versus 56% of Caucasians with 12% homozygotes (P<0.0001). Our findings suggest that the potentially unfavourable pattern of apo E allele distribution in Black South Africans does not result in increased CHD incidence due to protection by dietary and/or other life style related factors. The exceptionally low frequency of MTHFR mutant homozygotes in this population suggests that this polymorphism should not be regarded as an important CHD risk factor among Black South Africans.
Alleles↗
Apolipoprotein E genotype modulates the effect of black tea drinking on blood lipids and blood coagulation factors: a pilot study.
Apolipoprotein E (ApoE) genotype was determined in sixty-five subjects who had taken part in a 4-week randomized crossover trial to compare the effect of six mugs of black tea per day v. placebo on blood lipids and blood coagulation factors. Four ApoE genotype variants (seven E2/E3, forty-five E3/E3, twelve E3/E4 and one E4/E4) were found. ApoE allele frequency was within the range typical for Caucasian populations (ApoE-E2 5.4%; ApoE-E3 83.8%; ApoE-E4 10.8%). Individuals bearing at least one E4 allele had substantially higher levels of serum total cholesterol, LDL cholesterol and triacylglycerols. Mean plasminogen activator inhibitor (PAI-1) activity was higher in ApoE-E4 allele-bearing individuals (E3/E4 + E4/E4, 11.89 (SE 1.27) U/ml; E3/E3, 9.19 (SE 0.80) U/ml; E2/E3, 7.21 (SE 1.04) U/ml, P values of E4-group v. E3 and E2 being respectively 0.093 and 0.030). These unexpected findings imply that elevated PAI-1 activity may be a hitherto unrecognized additional factor involved in the increased cardiovascular disease risk associated with apoE-E4 allele. The interactions between tea drinking and genotype were also examined. In the E3/E3 homozygotes, HDL-cholesterol was significantly reduced in the tea period (mean placebo 1.54 mmol/l v. mean tea 1.50 mmol/l, P = 0.027). In the E2/E3 group, triacylglycerol concentration was significantly reduced (mean placebo 1.18 mmol/l v. mean tea 1.09 mmol/l, P = 0.039). Tea also caused a significant decrease of PAI-1 activity in the subjects with E2/E3 genotype (mean placebo 7.21 U/ml v. mean tea 5.88 U/ml, P = 0.007). In the other two genotype groups, there was no significant effect of tea. The results indicate that tea drinking has a beneficial effect on some cardiovascular disease risk-associated factors, especially in E2 allele-bearing individuals. Dietary intervention may be particularly effective in population groups with certain genetic characteristics.
Adult↗
Quantitation of DNA from exfoliated colonocytes isolated from human stool surface as a novel noninvasive screening test for colorectal cancer.
The only widely used screening test for early detection of colorectal cancer, the fecal occult blood test, lacks both sensitivity and specificity because it relies upon incidental bleeding rather than the neoplastic process. With the purpose of developing a new noninvasive diagnostic approach, we quantified DNA extracted from cells isolated from the surface of human stools by a novel procedure. Stools collected from 28 healthy individuals, 17 colorectal cancer patients, and 11 colorectal polyp patients were analyzed. A stool DNA index (SDNAI), expressed as DNA amount in nanograms per gram of stool, had a remarkable 4.5-fold difference in mean values between colorectal cancer patients and healthy people of comparable age. SDNAI was 2133 +/- 407 in the cancer group versus 469 +/- 65 in healthy people of the older (> 50 years) age group (P = 0.0005). The difference was independent of tumor location and size. If 700 ng of DNA/g of stool was taken as a cutoff SDNAI value in discrimination between older healthy people and cancer patients, sensitivity and specificity values reached 1.00 and 0.81, respectively. Age dependence of SDNAI was demonstrated by substantially lower SDNAI values (mean, 227 +/- 41) in younger healthy individuals. Polyp patients sometimes displayed elevated SDNAI values, but considerable variation was observed (mean, 1215 +/- 548). These preliminary findings indicate that SDNAI provides a novel, simple, and powerful noninvasive test for colorectal cancer early detection and screening. The fundamental advantage of the SDNAI is that it directly characterizes colonic epithelium involved in carcinogenesis.
Adult↗
Comparison of metabolic effects of vegetables and teas with colorectal proliferation and with tumour development in DMH-treated F344 rats.
The aim of this study was to screen potentially chemopreventive vegetables and teas for their effects as human dietary components for the colorectal epithelium and also to seek biomarkers of preventive efficacy. Groups of F344 rats were adapted to a human basal diet supplemented with vegetables or teas, having known contents of glucosinolates, polyphenols and anti-oxidants. Both inductions and suppressions were found for overall glutathione S-transferase (GST) and quinone reductase activities. The mitotic index (MI) showed a three-fold range between groups, with substantial reductions by black tea, spinach, petit pois and peppers. Changes to PCNA labelling index and proliferation zone were marginal. No correlation was found between colonic and hepatic enzyme activities, nor with glucosinolate intake. Colonic MI was associated with the activity ratio GST(hepatic)/GST(colonic) (r = 0.49, P < 0.002), possibly reflecting a need for direct induction rather than exposure to products of hepatic conjugation.
Animals↗
Diet-genotype interactions: an example from tea.
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Aged↗
Transplacental and transgeneration carcinogenic effect of 7,12-dimethylbenz[a]anthracene: relationship with ras oncogene activation.
Transgeneration transmission of the carcinogenic action of 7,12-dimethylbenz[a]anthracene (DMBA) was studied in two generations of mice using transplacental DMBA initiation followed by postnatal skin tumor promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA) in the first generation (F0) and only promotion in the second generation (F1). Local application of TPA resulted in increased skin tumor yield in both the in utero DMBA-exposed mice and their progeny (P = 0.0002 and P = 0.0941 respectively compared to control). Similarly, lung tumor incidence was increased in the two generations of mice (P less than 0.0001 and P = 0.0080 respectively). The results suggest transgeneration transfer of the effect of DMBA. A to T mutation at the second base of codon 61 of the Ha-ras oncogene was found in skin tumors of DMBA-exposed mice, but not in tumors induced by TPA without initiation. Analysis of Ki-ras codon 61 in seven lung tumors from DMBA-treated mice revealed three types of mutation: two cases with CA[C or G or T], one case with CCA and one case with CTA (the remaining cases having only the wild type). Six of these mice also had skin tumors, which contained A to T mutation at the second base of codon 61 of the Ha-ras gene in five cases. Thus mutations of different ras genes were found in skin and lung tumors from the same animals. In the progeny (F1) of DMBA-exposed F0 mice, only skin tumor samples were available for oncogene analysis and none contained the Ha-ras mutation. The results confirm our previous finding that initiation of skin and lung tumorigenesis can be transmitted transgenerationally. On the other hand, our data from a limited number of skin tumors suggests that ras gene mutation may not be critically involved in this transmission.
9,10-Dimethyl-1,2-benzanthracene↗
Perinatal and multigenerational effect of carcinogens: possible contribution to determination of cancer susceptibility.
Perinatal exposure to carcinogens may contribute to the determination of susceptibility to cancer in two situations: a) exposure in utero of embryonal or fetal somatic cells to carcinogens, and b) prezygotic exposure of the germ cells of one or both parents to carcinogens. Epidemiological as well as experimental studies demonstrate that exposure to carcinogens in utero increases the occurrence of cancer postnatally. Studies with experimental animals suggest that prezygotic exposure of germ cells to carcinogens can result in an increased incidence of cancer not only in immediate but also in subsequent generations. Although several studies suggest a transgeneration effect of carcinogens in human populations, the evidence cannot yet be considered conclusive. In particular, while some hypotheses can be advanced, the mechanism(s) by which increased susceptibility or predisposition to cancer may be transmitted via the germ cells has not yet been clarified. In conjunction with exposure both in utero and prezygotically, it is important to consider postnatal exposure to possible tumor-promoting agents. Results from experimental animals suggest that oncogenes can be activated transplacentally, and human studies indicate that tumor-suppressor gene inactivation may be involved in the transgenerational effect of carcinogens.
Animals↗
Tissue-specific activating mutations of Ha- and Ki-ras oncogenes in skin, lung, and liver tumors induced in mice following transplacental exposure to DMBA.
Transplacental carcinogenesis represents a good model in which to study the involvement of tissue-specific oncogene activation in carcinogenesis because a single exposure to a carcinogen induces tumors at various sites. We tested tumors of the skin, liver, and lung produced in mice after transplacental 7,12-dimethylbenz[a]-anthracene (DMBA) exposure for possible activation of ras genes. XbaI restriction fragment-length polymorphism analysis has shown that exposure to DMBA in utero may result in appearance of A----T transversion at the second position of codon 61 of Ha-ras oncogene in skin and liver tumors but not in lung tumors. Moreover, DNA samples isolated from spontaneous and DMBA-induced lung and liver tumors were analyzed for mutations at the same position of Ki-ras oncogene using differential hybridization with specific oligonucleotides. Among five spontaneous lung tumors, three cases of A----G transition, and one case of A----T transversion were found, whereas four of ten lung tumors of DMBA-treated animals were positive for A----T mutation. No Ki-ras mutation was detected in one spontaneous and four DMBA-induced hepatomas. In two cases, we revealed Ki-ras A----T mutation in the lung tumor and Ha-ras mutation in the liver tumor taken from the same animal. These results indicate first that DMBA treatment may induce A----T mutation at the second position of codon 61 both in Ha-ras and in Ki-ras and, second, that the role of different activated oncogenes in carcinogenesis may differ, depending on the tissue in which the tumor develops.
9,10-Dimethyl-1,2-benzanthracene↗
Increased tumour incidence and skin tumour promotion in two generations of descendants of 7,12-dimethylbenz[a]anthracene-treated pregnant mice.
Many experiments suggest the possibility of hereditary transmission of a predisposition to developing cancer. If this is the case, the progeny of animals exposed to carcinogens during embryogenesis should bear initiated cells. In order to examine this possibility, offspring of mice exposed to 7,12-dimethyl-benz[a]anthracene in utero were treated cutaneously with a tumour promoter, 12-O-tetradecanoylphorbol-13-acetate. This treatment resulted in the development of skin tumours, i.e., papillomas and carcinomas. Moreover, various tumours also developed in many internal organs, and particularly in the lung. These findings suggest that exposure to carcinogens may not only increase cancer risk in subsequent generations, but also considerably reinforce sensitivity to tumour-promoting factors, which by themselves may pose no threat to an unexposed population.
9,10-Dimethyl-1,2-benzanthracene↗
Persistence of carcinogenic effect in intact progeny of mice treated transplacentally with 7,12-dimethylbenz[a]anthracene.
Pregnant SHR mice were treated once with 7,12-dimethylbenz[a]anthracene (DMBA) on days 17-19 of gestation. F1 and F2 descendants of these mice received multiple skin applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) twice a week for 24 weeks beginning at 12 weeks of age, or applications of solvent alone. The increase in the frequency of skin tumours in F1 and F2 descendants was reported elsewhere. In addition, we report here an increase in overall numbers of tumor-bearing animals, independently of TPA treatment both in F1 and F2 groups compared to respective control groups. Separate statistical analyses were performed for lung tumours, mammary gland tumours, leukaemias and lymphomas. In both generations of descendants of DMBA-treated mothers lung tumour incidence was considerably increased and differed significantly (maximal P-value = 0.003) from control values. Local applications of TPA resulting in strong skin tumour promoting effect described in our previous paper (Napalkov et al., Carcinogenesis, 8(3) (1987) 381) did not produce any significant change in the rates of other types of tumours. The results of the present study provide additional evidence in support of the hypothesis on possibility of hereditary transmission of carcinogenic action of certain chemical compounds.
9,10-Dimethyl-1,2-benzanthracene↗
Promotion of skin tumours by TPA in the progeny of mice exposed pre-natally to DMBA.
Pregnant SHR mice were treated once with 7,12-dimethylbenz[a]anthracene (DMBA) on day 17-19 of gestation, and F1 and F2 descendants received multiple skin applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) twice a week for 24 weeks beginning at 12 weeks of age. Post-natal promoter treatment resulted in a high incidence of skin tumours in F1 and F2 mice (37.3 and 19.7%, respectively), whereas only 6.6% of control animals treated with TPA only developed skin tumours. DMBA was shown previously to be capable of initiating skin carcinogenesis transplacentally; however, our results on the second generation provide suggestive evidence of hereditary transmission of at least part of the initiating action of this carcinogen.
9,10-Dimethyl-1,2-benzanthracene↗