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Abstracts

Life Extension Magazine December 2011
Abstracts

Alcohol and Cancer

Alcohol attributable burden of incidence of cancer in eight European countries based on results from prospective cohort study.

OBJECTIVE: To compute the burden of cancer attributable to current and former alcohol consumption in eight European countries based on direct relative risk estimates from a cohort study. DESIGN: Combination of prospective cohort study with representative population based data on alcohol exposure. Setting Eight countries (France, Italy, Spain, United Kingdom, the Netherlands, Greece, Germany, Denmark) participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. PARTICIPANTS: 109,118 men and 254,870 women, mainly aged 37-70. MAIN OUTCOME MEASURES: Hazard rate ratios expressing the relative risk of cancer incidence for former and current alcohol consumption among EPIC participants. Hazard rate ratios combined with representative information on alcoholconsumption to calculate alcohol attributable fractions of causally related cancers by country and sex. Partial alcohol attributable fractions for consumption higher than the recommended upper limit (two drinks a day for men with about 24 g alcohol, one for women with about 12 g alcohol) and the estimated total annual number of cases of alcohol attributable cancer. RESULTS: If we assume causality, among men and women, 10% (95% confidence interval 7 to 13%) and 3% (1 to 5%) of the incidence of total cancer was attributable to former and current alcohol consumption in the selected European countries. For selected cancers the figures were 44% (31 to 56%) and 25% (5 to 46%) for upper aerodigestive tract, 33% (11 to 54%) and 18% (-3 to 38%) for liver, 17% (10 to 25%) and 4% (-1 to 10%) for colorectal cancer for men and women, respectively, and 5.0% (2 to 8%) for female breast cancer. A substantial part of the alcohol attributable fraction in 2008 was associated with alcohol consumption higher than the recommended upper limit: 33,037 of 178,578 alcohol related cancer cases in men and 17,470 of 397,043 alcohol related cases in women. CONCLUSIONS: In western Europe, an important proportion of cases of cancer can be attributable to alcohol consumption, especially consumption higher than the recommended upper limits. These data support current political efforts to reduce or to abstain from alcohol consumption to reduce the incidence of cancer.

BMJ. 2011 Apr 7;342:d1584.

DNA adducts from acetaldehyde: implications for alcohol-related carcinogenesis.

Alcoholic beverage consumption is classified as a known human carcinogen, causally related to an increased risk of cancer of the upper gastrointestinal tract. The formation of acetaldehyde from ethanol metabolism seems to be the major mechanism underlying this effect. Acetaldehyde is carcinogenic in rodents and causes sister chromatid exchanges and chromosomal aberrations in human cells. The best-studied DNA adduct from acetaldehyde is N(2)-ethyl-2'-deoxyguanosine, which is increased in liver DNA obtained from ethanol-treated rodents and in white blood cells obtained from human alcohol abusers. However, the carcinogenic relevance of this adduct is unclear in view of the lack of evidence that it is mutagenic in mammalian cells. A different DNA adduct, 1,N(2)-propano-2'-deoxyguanosine (PdG), can also be formed from acetaldehyde in the presence of histones and other basic molecules. PdG has been shown to be responsible for the genotoxic and mutagenic effects of crotonaldehyde. The PdG adduct can exist in either of two forms: a ring-closed form or a ring-opened aldehyde form. Whereas the ring-closed form is mutagenic, the aldehyde form can participate in the formation of secondary lesions, including DNA-protein cross-links and DNA interstrand cross-links. The formation of these types of complex secondary DNA lesions resulting from PdG may explain many of the observed genotoxic effects of acetaldehyde described above. Repair of PdG and its associated adducts is complex, involving multiple pathways. Inherited variation in the genes encoding the proteins involved in the repair of PdG and its secondary adducts may contribute to susceptibility to alcoholic beverage-related carcinogenesis.

Alcohol. 2005 Apr;35(3):187-93.

The pathology of alcohol hangover.

Research on human subjects analyzing blood and urine samples determined biological correlates that may explain the pathology of alcohol hangover. These analyses showed that concentrations of various hormones, electrolytes, free fatty acids, triglycerides, lactate, ketone bodies, cortisol, and glucose were not significantly correlated with reported alcohol hangover severity. Also, markers of dehydration (e.g., vasopressin) were not significantly related to hangover severity. Some studies report a significant correlation between blood acetaldehyde concentration and hangover severity, but most convincing is the significant relationship between immune factors and hangover severity. The latter is supported by studies showing that hangover severity may be reduced by inhibitors of prostaglandin synthesis. Several factors do not cause alcohol hangover but can aggravate its severity. These include sleep deprivation, smoking, congeners, health status, genetics and individual differences. Future studies should more rigorously study these factors as well as biological correlates to further elucidate the pathology of alcohol hangover.

Curr Drug Abuse Rev. 2010 Jun;3(2):68-75.

Folate, methionine, and alcohol intake and risk of colorectal adenoma.

BACKGROUND: Reduced methylation of DNA may contribute to loss of the normal controls on proto-oncogene expression. In humans, hypomethylation of DNA has been observed in colorectal cancers and in their adenomatous polyp precursors. Accumulation of DNA methylation abnormalities, observed during progression of human colorectal neoplasia, may be influenced by certain dietary factors. The apparent protective effect of fresh fruits and vegetables, the major folate sources, on colorectal cancer incidence suggests that a methyl-deficient diet contributes to occurrence of this malignancy. Low dietary folate and methionine and high intake of alcohol may reduce levels of S-adenosylmethionine, which is required for DNA methylation. PURPOSE: To determine if dietary factors that may influence methyl availability are related to colorectal adenomas, we prospectively examined the association of folate, methionine, and alcohol intakes and risk of colorectal adenoma. METHODS: We assessed dietary intake for a 1-year period for women of the Nurses' Health Study, started in 1976, and for men of the Health Professionals Follow-up Study, started in 1986--using a semiquantitative food frequency questionnaire. Adenomatous polyps of the left colon or rectum were diagnosed in 564 of 15,984 women who had had an endoscopy between 1980 and 1990 and in 331 of 9,490 men who had undergone an endoscopy between 1986 and 1990. RESULTS: High dietary folate was inversely associated with risk of colorectal adenoma in women (multivariate relative risk [RR] = 0.66; 95% confidence interval [CI] = 0.46-0.95 between high and low quintiles of intake) and in men (RR = 0.63; 95% CI = 0.41-0.98) after adjusting for age, family history, indications for endoscopy, history of previous endoscopy, total energy intake, saturated fat intake, dietary fiber, and body mass index. Relative to nondrinkers, drinkers of more than 30 g of alcohol daily (about two drinks) had an elevated risk of adenoma (in women, RR = 1.84, 95% CI = 1.19-2.86; in men, RR = 1.64, 95% CI = 0.92-2.93). Methionine intake was inversely associated with risk of adenomas 1 cm or larger (RR = 0.62; 95% CI = 0.46-0.85, combining men and women). CONCLUSIONS: Folate, alcohol, and methionine could influence methyl group availability, and a methyl-deficient diet may be linked to early stages of colorectal neoplasia. A dietary pattern that increases methyl availability could reduce incidence of colorectal cancer. IMPLICATIONS: These data support efforts to increase dietary folate in segments of the population having diets with low intakes of this nutrient.

J Natl Cancer Inst. 1993 Jun 2;85(11):875-84.

Dietary folate intake, alcohol, and risk of breast cancer in a prospective study of postmenopausal women.

Low B-vitamin intake may increase risk of breast cancer through decreased DNA repair capacity. Alcohol intake increases risk for breast cancer, with evidence from prospective studies of an interaction between alcohol and folate. We explored dietary intake of folate and other B vitamins with risk of breast cancer in a cohort study of 34,387 postmenopausal women. To measure diet, we mailed a food frequency questionnaire; we estimated nutrient intakes and categorized them into four levels: <10th, 11th-30th, 31st-50th, and >50th percentiles. Through 12 years of follow-up, we identified 1,586 cases of breast cancer in the cohort at risk. We estimated relative risks (RRs) and 95% confidence intervals (CIs) through Cox regression models adjusted for age, energy, and other risk factors. Women in the lowest 10th percentile of folate intake from diet alone were at modestly increased risk of breast cancer relative to those above the 50th percentile: RR = 1.21 (95% CI = 0.91--1.61). We examined the joint association of folate intake and alcohol use on risk of breast cancer, with the reference group defined as women with high folate (>50th percentile) and no alcohol use. The RRs of breast cancer associated with low dietary folate intake were 1.08 (95% CI = 0.78--1.49) among nondrinkers, 1.33 (95% CI = 0.86--2.05) among drinkers of < or = 4 gm per day, and 1.59 (95% CI = 1.05--2.41) among drinkers of > 4 gm per day. These results suggest that the risks of postmenopausal breast cancer may be increased among women with low intakes of folate if they consume alcohol-containing beverages.

Epidemiology. 2001 Jul;12(4):420-8.

Inhibition of inflammation and carcinogenesis in the lung and colon by tocopherols.

Tocopherols, which exist in alpha, beta, gamma, and delta forms, are antioxidative nutrients also known as vitamin E. Although alpha-tocopherol (alpha-T) is the major form of vitamin E found in the blood and tissues, gamma- and delta-T have been suggested to have stronger anti-inflammatory activities. In the present study, using a tocopherol mixture that is rich in gamma-T (gamma-TmT, which contains 57%gamma-T), we demonstrated the inhibition of inflammation as well as of cancer formation and growth in the lung and colon in animal models. When given in the diet at 0.3%, gamma-TmT inhibited chemically induced lung tumorigenesis in the A/J mice as well as the growth of human lung cancer cell H1299 xenograft tumors. gamma-TmT also decreased the levels of 8-hydroxydeoxyguanosine, gamma-H2AX, and nitrotyrosine in tumors. More evident anti-inflammatory and cancer preventive activities of dietary gamma-TmT were demonstrated in mice treated with azoxymethane and dextran sulfate sodium. These results demonstrate the antioxidative, anti-inflammatory, and anticarcinogenic activities of tocopherols.

Ann N Y Acad Sci. 2010 Aug;1203:29-34.

The multifaceted therapeutic potential of benfotiamine.

Thiamine, known as vitamin B(1), plays an essential role in energy metabolism. Benfotiamine (S-benzoylthiamine O-monophoshate) is a synthetic S-acyl derivative of thiamine. Once absorbed, benfotiamine is dephosphorylated by ecto-alkaline phosphatase to lipid-soluble S-benzoylthiamine. Transketolase is an enzyme that directs the precursors of advanced glycation end products (AGEs) to pentose phosphate pathway. Benfotiamine administration increases the levels of intracellular thiamine diphosphate, a cofactor necessary for the activation transketolase, resulting in the reduction of tissue level of AGEs. The elevated level of AGEs has been implicated in the induction and progression of diabetes-associated complications. Chronic hyperglycemia accelerates the reaction between glucose and proteins leading to the formation of AGEs, which form irreversible cross-links with many macromolecules such as collagen. In diabetes, AGEs accumulate in tissues at an accelerated rate. Experimental studies have elucidated that binding of AGEs to their specific receptors (RAGE) activates mainly monocytes and endothelial cells and consequently induces various inflammatory events. Moreover, AGEs exaggerate the status of oxidative stress in diabetes that may additionally contribute to functional changes in vascular tone control observed in diabetes. The anti-AGE property of benfotiamine certainly makes it effective for the treatment of diabetic neuropathy, nephropathy and retinopathy. Interestingly, few recent studies demonstrated additional non-AGE-dependent pharmacological actions of benfotiamine. The present review critically analyzed the multifaceted therapeutic potential of benfotiamine.

Pharmacol Res. 2010 Jun;61(6):482-8.

In vivo antioxidant activity of procyanidin-rich extracts from grape seed and pine (Pinus maritima) bark in rats.

BACKGROUND: In vitro evidence exists for the potential antioxidant benefits of procyanidin-rich extracts, but in vivo studies are scarce. We have evaluated the effects of selected procyanidin-rich extracts on oxidative stress in rats in condition of prolonged consumption of these compounds and also after single administration i.e. in postprandial conditions. METHODS: Rats were fed for 8 weeks with diets supplemented with either a grape seed extract (GE), a pine bark extract (PE), or a high-degree polymerized pine bark extract (HPE). An additional study was performed in order to assess the postprandial effect of these extracts on plasma antioxidant capacity. The ferric-reducing antioxidant power (FRAP) and thiobarbituric acid-reactive substances (TBARS) were determined in plasma. For lipid peroxidation study of heart tissue, homogenates were prepared and TBARS were measured after lipid peroxidation induced by FeSO4-ascorbate. RESULTS: After 8 weeks of dietary treatment, total antioxidant capacity in plasma was significantly higher in the GE and PE groups as compared with the other two groups. Plasma TBARS concentrations and heart susceptibility to peroxidation were not significantly different between the groups. In the postprandial state, by comparing plasma antioxidant capacity 2 hours after ingestion of the different procyanidin-rich extracts (500 mg/kg body weight), we observed that FRAP values were higher in the procyanidin-rich extracts groups as compared with the control group. Moreover, plasma FRAP concentration was significantly higher in the GE group as compared with the other groups. CONCLUSION: The results of the present experiment constitute positive evidence for an in vivo antioxidant effect at the plasma level of procyanidin-containing plant extracts.

Int J Vitam Nutr Res. 2006 Jan;76(1):22-7.

Silymarin in the treatment of chronic liver diseases: past and future.

In the treatment of chronic liver diseases adequate therapy can be chosen only in the knowledge of pathogenetic processes. In the liver diseases caused by oxidative stress (alcoholic and non-alcoholic fatty liver and steatohepatitis, drug and compound induced liver toxicity) the antioxidant drugs, like silymarin, in chronic hepatitis caused by hepatitis B and hepatitis C virus, combined peginterferon and nucleosid treatments are the primary therapy modalities to be selected. The main effects of silymarin are the membrane stabilising and antioxidant effects, it is able to help the liver cell regeneration, it can decrease the inflammatory reaction and inhibit the fibrogenesis in the liver. These results have been established by experimental and clinical trials. According to open studies, the long administration of silymarin significantly increased the survival time of patients with alcohol-induced liver cirrhosis. Recently it was demonstrated that high-dosage silibinin infusion treatment could significantly decrease the number of hepatitis C viruses after four-week application. On the basis of the results with the methods of molecular biology, silymarin is able to decrease significantly tumor cell proliferation, angiogenesis as well as insulin resistance. These results support the administration of silymarin preparations in the therapy of chronic liver diseases, especially in alcoholic and non-alcoholic steatohepatitis in current clinical practice, and as it can be awaited, also in the future. In some neoplastic diseases they could also be administered as adjuvant therapy.

Orv Hetil. 2008 Dec 21;149(51):2413-8.

Chlorophyll, chlorophyllin and related tetrapyrroles are significant inducers of mammalian phase 2 cytoprotective genes.

Plant chlorophylls and carotenoids are highly colored, conjugated polyenes that play central roles in photosynthesis. Other porphyrins (tetrapyrroles), such as cytochromes, which are structurally related to chlorophyll, participate in redox reactions in many living systems. An unexpected new property of tetrapyrroles, including tetramethyl coproporphyrin III, tetrabenzoporphine, copper chlorin e4 ethyl ester, and of carotenoids including zeaxanthin and alpha-cryptoxanthin is their ability to induce mammalian phase 2 proteins that protect cells against oxidants and electrophiles. The capacity of these compounds to induce the phase 2 response depends upon their ability or that of their metabolites to react with thiol groups, a property shared with all other classes of phase 2 inducers, which show few other structural similarities. Pseudo second-order rate constants of these inducers are correlated with their potency in inducing the phase 2 enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) in murine hepatoma cells. One of the most potent inducers was isolated from chlorophyllin, a semisynthetic water-soluble chlorophyll derivative. Although chlorophyll itself is low in inducer potency, it may nevertheless account for some of the disease-protective effects attributed to diets rich in green vegetables because it occurs in much higher concentrations in those plants than the widely studied 'phytochemicals.'

Carcinogenesis. 2005 Jul;26(7):1247-55.