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PubMed2005

Evidence of a decrease in nitric oxide-storage molecules following acute hypoxia and/or hypobaria, by means of chemiluminescence analysis.

Nitrate, nitrite, and other nitroso compounds (NOxs) had been proposed as possible nitric oxide (NO) storage molecules. The present work examines, by means of chemiluminescence analysis, changes in NOx serum levels in rats 1 h before and 24, 48, and 72 h after exposure to acute hypobaric hypoxia (HH; barometric pressure [P(B)] 225 mmHg, oxygen partial pressure [PO2] 48 mmHg), normobaric hypoxia (NH; P(B) 716 mmHg [Jaén city], PO2 48 mmHg), hypobaric normoxia (HN; P(B) 225 mmHg, PO2 150 mmHg), and normobaric normoxia (NN; P(B) 716 mmHg, PO2 150 mmHg) the latter as a control group. Results show a decrease in NOx levels, which reached significance 24 h after exposure in HH animals, 4 h after exposure in the HN and NH groups, and persisted after 48 h of exposure in the HN group. NOx determinations were also performed in brain (cerebral cortex, hippocampus, decorticated brain [basal ganglia-brainstem] and cerebellum), liver, kidney, lung, and heart homogenates, 72 h after the experiment, to detect persistent effects when serum NOx levels had returned to basal values. Only in cerebellum (HN group) and hippocampus (HN and NH groups) were NOx levels significantly lower than in controls. We conclude that not only acute hypobaric hypoxia but also either hypobaria or hypoxia alone induce changes in NOx serum levels. Moreover, all three episodes involve a decrease in NOxs, greater and longer-lasting in hypoxia alone than in hypobaria and hypoxia together. The exhaustion of these NO-storage molecules could be critical when, as during a hypoxic episode, the L-arginine/NOS pathway is impaired.

Adaptation, Physiological↗
PubMed2001

Residential water source and the risk of childhood brain tumors.

Gestation may represent a window of susceptibility to transplacental effects of environmental exposures, including chemicals in water. The N-nitroso compounds (NNC), a class of chemicals with demonstrated neurocarcinogenic potential, include substances detected in drinking water. We used data from a study of possible risk factors for childhood brain tumors (CBT) to investigate the association of source of residential drinking water during pregnancy and CBT occurrence among offspring. In addition, dipstick measurements were made of nitrates and nitrites in tap water for the subset of women living in the same home they had lived in during their pregnancies. Population-based CBT cases (n = 540) and controls (n = 801) were identified in three regions including Los Angeles County, and the San Francisco Bay Area of California, and the Seattle-Puget Sound area of western Washington state. Overall, we observed no increased risk of CBT in offspring associated with wells as the source of residential water. However, an increased risk of CBT [odds ratio (OR) = 2.6; 95% confidence interval (CI), = 1.3-5.2] was observed in western Washington among offspring of women who relied exclusively on well water, and a decreased risk of CBT (OR = 0.2; 95% CI, 0.1-0.8) was observed in Los Angeles County. Among the small subset of subjects for whom dipstick measurements of tap water were available, the risk of CBT associated with the presence of either measurable nitrite and/or nitrate was 1.1 (95% CI, 0.7-2.0). Given the crude measurement method employed and because measurements often were obtained years after these pregnancies occurred, the relevance of the dipstick findings is unclear. The lack of consistency in our findings related to residential water source does not support the hypothesis of increased risk related to consumption of well water; however, regional differences in well water content may exist, and the increased risk observed in western Washington deserves further evaluation.

Adolescent↗
PubMed2006

Genotoxic and carcinogenic risk to humans of drug-nitrite interaction products.

The large majority of N-nitroso compounds (NOC) have been found to produce genotoxic effects and to cause tumor development in laboratory animals; four NOC have been classified by the International Agency for Research on Cancer (IARC) as probably and another 15 as possibly carcinogenic to humans. A considerable fraction of drugs are theoretically nitrosatable due to the presence of amine, amide or other groups which by reacting with nitrite in the gastric environment, or even in other sites, can give rise to the formation of NOC, and in some cases other reactive species. This review provides a synthesis of information on the chemistry of NOC formation, the carcinogenic activity of NOC in animals and humans and the inhibitors of nitrosation reactions. It contains information on the drugs which have been tested for the formation of NOC by reaction with nitrite and the genotoxic-carcinogenic effects of their nitrosation products. In an extensive search we have found that 182 drugs, representing a wide variety of chemical structures and therapeutic activities, were examined in various experimental conditions for their ability to react with nitrite, and 173 (95%) of them were found to form NOC or other reactive species. Moreover, 136 drugs were examined in short-term genotoxicity tests and/or in long-term carcinogenesis assays, either in combination with nitrite or using their nitrosation product, in order to establish whether they produce genotoxic and carcinogenic effects; 112 (82.4%) of them have been found to give at least one positive response. The problem of endogenous drug nitrosation is largely unrecognized. Only a small fraction of theoretically nitrosatable drugs have been examined for the possible formation of genotoxic-carcinogenic NOC, guidelines for genotoxicity testing of pharmaceuticals do not indicate the need of performing the appropriate tests, and patients are not informed that the drug-nitrite interaction and the consequent risk can be reduced to a large extent by consuming the nitrosatable drug with ascorbic acid.

Animals↗
PubMed2002

West Coast study of childhood brain tumours and maternal use of hair-colouring products.

The immature nervous system of the fetus is characterised by rapid cell growth and division and is particularly vulnerable to carcinogens and mutagens. Several epidemiological studies have reported an increased risk for childhood brain tumours (CBT) associated with exposure to N-nitroso compounds (NOC). Hair-colouring products (hair "dyes") that contain NOC-related aromatic amines have shown mutagenicity in vitro and carcinogenic properties in vivo. The potential public health impact of the relationship between hair dye use and carcinogenesis has prompted epidemiological research, given that a large proportion of American women have used hair dyes. A large population-based case-control study was conducted on the west coast of the USA to investigate risk factors for CBT including exposure to NOC. Eligible CBT patients (<20 years of age and diagnosed between 1984 and 1991) were identified from cancer registries in Los Angeles County, the San Francisco Bay Area in California and the Seattle area in Washington state. A total of 540 biological mothers of these children were interviewed, and 801 control subjects who were frequency matched to the CBT patients on birth year and sex were obtained using random digit dialling. Mothers were asked details about personal use of hair dyes during the index pregnancy including frequency of use, trimester of use and type of dye used. Results from age- and sex-adjusted unconditional logistic regression analyses showed no association between risk for CBT and use of hair dyes 1 month before and/or during pregnancy nor during specific trimesters. A nearly twofold increased risk for CBT was associated with single-interval use during the 1 month before pregnancy, but the confidence interval (CI) was imprecise and the estimate was not different from unity (OR = 1.9, 95% CI [0.5, 7.0]). Exclusive use of permanent dye, temporary dye or hair darkeners was not associated with risk for CBT. A twofold increased risk (OR = 2.0, 95% CI [0.83, 4.7]) was observed with exclusive use of semi-permanent dye during the month before or during pregnancy. Exclusive use of semi-permanent dye during the month before pregnancy and/or first trimester also was associated with an elevated risk for CBT, again not different from unity and with an imprecise CI (OR = 2.5, 95% CI = [0.58, 10.3]). There was no evidence of an association between risk for CBT by histological subtypes and use of hair dyes during the index pregnancy or the month before conception. Together with results from previous studies, these results provide no consistent evidence of an association between risk for CBT and use of hair dyes during pregnancy.

Adolescent↗
PubMed1986

The role of ascorbic acid in carcinogenesis.

Vitamin C is an essential nutrient whose protective role in carcinogenesis has been discussed for more than 50 years. Epidemiologic studies suggest that the consumption of vitamin C-rich foods is associated with a lower risk of cancers of the esophagus and stomach. The observation that cancer patients have low leukocyte vitamin C levels led to therapeutic trials the results of which are controversial; the hypothesis that vitamin C acts like a drug must be questioned. On the other hand, ascorbic acid interacts with various tumor-inducing compounds, such as the precursors of N-nitroso compounds, to prevent the formation of tumors. Experiments with animals and cell cultures indicate that ascorbic acid can interfere with the metabolism of tumor promoters. It has also been postulated that ascorbic acid helps to prevent cancer by enhancing cellular immunity. In general, evidence suggests that vitamin C can inhibit the formation of some carcinogens.

Animals↗
PubMed1993

Detection of nitric oxide production from a perfused organ by a luminol-H2O2 system.

Nitric oxide, thought to be the endothelium-derived relaxing factor (EDRF), is involved in intra- and intercellular signalling in various tissues. A system for the continuous detection of NO in the picomolar range from a perfused organ is described. The detection is based upon the chemiluminescence reaction between NO and the luminol (5-amino-2,3-dihydro-1,4-phthalazinedione)-H2O2 system. The chemiluminescence is due to the formation of peroxynitrite from NO and H2O2. The luminol-H2O2 system is specifically reactive to NO, so that other nitrogen-containing compounds, (organic nitrite, organic nitrate, and thio-nitroso compounds) or endothelium-derived compounds do not interfere. The limit of determination was approximately 100 fM. This system has been used to measure continuous NO release from isolated perfused rat kidney and the simultaneous changes of perfusion pressure. In Wistar rats basal NO release was 85 +/- 11 fmol/min-1 (g of kidney weight)-1 (39 pM in the perfusate), and acetylcholine increased NO release dose dependently with a concomitant pressure reduction. The changes in NO release were always associated with mirror image changes in the perfusion pressure. Simple pressure reduction did not interfere with the chemiluminescence. Precise titration data as well as results of some preliminary experiments using this method are presented.

Animals↗
PubMed1990

Microsomally-mediated denitrosation of nitrosoguanidinium compounds.

A major metabolic fate of 1-methyl-2-nitro-1-nitrosoguanidine (MNNG) and nitrosocimetidine (NC) in rodents is denitrosation to generate the unmodified, parent guanidinium compound. MNNG is a potent, locally-acting carcinogen. NC is the nitrosated derivative of cimetidine, an important clinical drug administered orally for the treatment of stomach ulcers. Contrary to expectations based on the results of various short-term in vitro tests for carcinogenic potential, NC is not a carcinogen when administered to rats or mice. Rat liver microsomal enzymes have been found to be capable of catalyzing the denitrosation of MNNG, NC and an NC analog, 1,3-dimethyl-2-cyano-1-nitrosoguanidine (CyanoDMNG) in an NADPH-dependent reaction. The denitrosated guanidinium compound generated accounts for 50-70% of the nitroso compound metabolized in a microsomal incubate; nitrite is generated with a yield which represents 40-60% of the guanidinium compound produced. The cytochrome P450 inhibitors metyrapone, n-octylamine, 1-n-hexylimidazole and ellipticine inhibit the conversion of CyanoDMNG to 1,3-dimethyl-2-cyanoguanidine (Cyano-DMG) and nitrite. Microsomal NADPH-cytochrome c reductase activity is not perturbed by this series of organic compound inhibitors. Diethyl maleate at high concentrations weakly stimulates the reaction. The rates of production of the CyanoDMNG degradation products CyanoDMG, nitrite and nitrate are markedly diminished in nitrogen-saturated and in carbon dioxide-saturated microsomal incubates. Preincubating microsomes for 1 h at 37 degrees C prior to substrate and NADPH addition has no effect on the denitrosation activity. Kinetic analysis of the conversion of CyanoDMNG to CyanoDMG indicates a Km of 1.0 mM and a Vmax of 2.7 nmol/min/mg protein. Microsomes isolated from rats pretreated with the cytochrome P450 inducers pyrazole or phenobarbital show enhanced denitrosation activity. The denitrosation capacity of hamster liver microsomes is similar to that observed for rat microsomes.

Aminopyrine↗
PubMed1981

Mutagenicity of reaction products of sulpyrine with nitrite.

The mutagenicity of three N-nitroso compounds produced by the reaction of sulpyrine with nitrite, 1-diketobutyryl-1-phenyl-2-methyl-2-nitrosohydrazide hydrate (DPMN), 4-(N-methyl-N-nitroso) aminoantipyrine (MNAA) and 1-acetyl-1-methyl-2-nitroso-2-phenylhydrazine, was tested on Salmonella typhimurium TA100 and TA98. The mutagenicity of related compounds, 4-methyl-aminoantipyrine, 1-acetyl-1-methyl-2-phenylhydrazine, 4-hydroxyantipyrine, sulpyrine and sodium nitrite was also examined. DPMN and MNAA, which are main reaction products in the nitrosation of sulpyrine, and sodium nitrite were mutagenic to TA100, but not to TA98. The other compounds were not mutagenic to either strain. MNAA required metabolic activation with rat-liver microsomal preparation (S9 mix) for the mutagenic activity, while DPMN did not require S9 mix. The mutagenicity of DPMN was remarkably increased by the addition of L-cysteine or glutathione. The enhancing effect was proportional to the concentrations of cysteine (0.4-2.1 mumoles/plate) or glutathione (0.8-6.5 mumoles/plate) added.

Aminopyrine↗
PubMed1977

The mutagenicity of methylbenzylnitrosamine and its alpha-acetoxy derivatives.

Biological activity of the alpha-acetoxy derivatives of methylbenzylnitrosamine was evaluated using tester strains of Salmonella typhimurium. Compound III, oxidized on the benzyl moiety, was more toxic and more mutagenic than Compound IV, oxidized on the methyl side chain. Compound IV was weakly toxic and was non-mutagenic at the concentrations tested. The presence or absence of the uvrB repair system had no effect on the toxicity of either Compound II or IV. Neither the alpha-oxidized compounds nor the parent nitrosamine reverted the frameshift mutants. As a mutagen, Compound III was approximately as active as N-nitroso compounds not requiring metabolic activation, more active than alpha-acetoxy dialkylnitrosamines and less active than the cyclic alpha-acetoxynitrosopyrrolidine.

Carcinogens↗
PubMedDate not supplied

Metallothionein in physiological and physiopathological processes.

The multipurpose nature of MT that we have presented in this review has drawn attention from many different fields of research: biochemistry, molecular biology, toxicology, pharmacology, etc. In recent years, considerable advances have been made concerning the regulation of MT genes by metals. Little, however, is known at the molecular level about the mechanisms of MT induction by nonmetallic inducers such as growth factors. This is of particular interest since MT is highly expressed during liver regeneration, an event orchestrated by a series of growth stimulators and inhibitors. The significance of the nuclear distribution of MT in growing cells and what controls its translocation are questions that remain unanswered at the present time. The possibility that MT could participate in a DNA synthesis-related process through donation or abstraction of Zn to and from transcription factors has been inferred from in vitro studies. Such transfer mechanisms, however, have yet to be confirmed in vivo. Overexpression of MT is often accompanied by increased resistance towards a variety of alkylating agents and chemotherapeutic drugs. The mechanisms by which MT protects cells against these agents may depend on their distinct mode of toxic action. For some, MT cysteines can be the target of the direct attack from the parent compound. For others such as N-methyl-N-nitroso compounds, MT cysteines may serve as a sink for the reactive oxygen species now known to be derived from their metabolism. In either case, a primary consequence of such interactions is the release of the metals initially bound to MT. Therefore, the metal composition of MT appears to be an important factor to consider in determining the overall effect of MT in the resistance process.

Amino Acid Sequence↗
PubMed1975

The inactivation of bacteriophage R17 by ethylating agents: the lethal lesions.

The biological inactivation of bacteriophage R17 by ethyl methanesulphonate (EMS) and N-ethyl-N-nitrosourea (ENUA) has been studied. At the mean lethal dose for the first compound 8 moles ethyl are bound/mole RNA and with the nitroso compound 3.5 moles ethyl are bound. Analysis of the amounts of the different ethylated derivatives formed shows that the toxicity of the sulphonate can be accounted for by the formation of 3-ethylcytosine, O6-ethylguanine, 1-ethyladenine and chain breaks produced on the hydrolysis of ethyl phosphotriesters. With the nitroso derivative on the other hand, the sum of chain breaks and of bases alkylated on a position involved in specific hydrogen bonding between base pairs only accounts for 65% of the observed toxicity. The possibility that 3-ethyladenine may constitute a lethal lesion is discussed.

Alkylation↗
PubMed1999

Treatment of human cells with N-Nitroso(acetoxymethyl)methylamine: distribution patterns of piperidine-sensitive DNA damage at the nucleotide level of resolution are related to the sequence context.

The nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) present in tobacco smoke is a major carcinogen involved in tobacco-induced lung cancer. Its complex bioactivation along two pathways, which leads to methylation and pyridyloxobutylation of DNA, makes the study of NNK-induced DNA damage difficult. We selected two nitroso compounds, N-methyl-N-nitrosourea (MNU) and N-nitroso(acetoxymethyl)methylamine (NDMAOAc), with which to map NNK-induced DNA methylation frequency at every nucleotide position. We address the issue of how sequence context and complex chromatin structures, present in living cells, regulate the formation of modified purines through methylation generated by MNU and NDMAOAc. For comparison purposes, purified DNA was treated with dimethyl sulfate (DMS). We used ligation-mediated polymerase chain reaction to map and conduct a high-resolution footprinting analysis of the DNA damage along the p53 gene (exons 5-8), the ras gene family (exons 1 and 2 of H-, K-, and N-ras genes), and the c-jun promoter in living cells. The distribution of piperidine-sensitive DNA damage induced in cellular DNA and purified DNA by MNU or NDMAOAc was identical. MNU and NDMAOAc methylate more frequently the central guanines in a run of guanines, suggesting a regioselective mechanism for DNA methylation. In contrast, DMS methylates more frequently guanines at the 5'-end of a guanine run; this frequency decreased from the 5'- to the 3'-end. While the presence of adenines in a guanine run does not affect the distribution pattern, the presence of pyrimidines does change said pattern. Our data lead us to suggest that NNK would also methylate DNA sequences in a way similar to that of MNU or NDMAOAc. Footprinted areas of DNA methylated with MNU or NDMAOAc correspond to a consensus sequence for transcription factors AP-1, NF-Jun, CCAAT box, SP-1, and RSRF, as observed in c-jun promoters. Our results are in line with the fact that NNK metabolites, generated through the alpha-hydroxylation pathways, could potentially be mutagenic, since these activated metabolites can methylate guanines. In p53 and ras genes, the frequency of methylation of guanines parallels the frequency of mutations of those same guanines in lung cancer.

Base Sequence↗
PubMed1978

Chloroperoxidase-catalysed oxidation of 4-chloroaniline to 4-chloronitrosobenze.

The incubation of 4-chloroaniline with chloroperoxidase and H2O2 resulted in a rapid formation of 4-chloronitrosobenzene. This enzymic oxidation displayed a pH optimum at 4.4 with a Km of 8.1x10(-4)M and catalytic-centre activity of 312. The initial rate of the reaction was strongly affected by the presence of halide ions. 4-Chlorophenylhydroxylamine was even more rapidly converted into the nitroso compound. A reaction mechanism is proposed on the basis of currently accepted theory for the catalytic action of chloroperoxidae. A noteworthy aspect of this new reaction is the difference in the products previously reported for the action of classical peroxidases on anilines and the single nitroso product resulting from chloroperoxidase oxidation.

Aniline Compounds↗
PubMed1991

Evidence of a role for compounds derived from arginine in coronary response to serotonin in vivo.

Recent studies have demonstrated that a nitroso compound derived from L-arginine (Arg) may be the endothelium-derived relaxing factor (EDRF) released from vascular endothelium. Synthesis of EDRF from L-Arg is inhibited by analogues of Arg such as NG-monomethyl-L-arginine (L-NMMA) and N omega-nitro-L-arginine (L-NNA). We tested the role of compounds derived from Arg in the constriction of the proximal left anterior descending coronary artery (LAD) to serotonin in vivo by measuring responses before and during infusion of L-NMMA or L-NNA. In open-chest anesthetized dogs the LAD was perfused at constant pressure (80 mmHg) from a reservoir. Large-artery diameter was measured with piezoelectric crystals, and coronary flow was measured with an in-line electromagnetic flow probe. Intracoronary serotonin (5 and 50 micrograms/min) caused a dose-dependent constriction of the proximal LAD and increase in coronary flow. Intracoronary L-NMMA (2 mg/min) or L-NNA (2 mg/min) augmented the constriction to serotonin, whereas the increase in coronary flow was blunted only by L-NNA. L-Arg (10 mg/min, intracoronary) alone did not alter either the large-artery constriction or the increase in flow to serotonin; however, it prevented the enhanced constriction to serotonin following L-NMMA. Constriction to the endothelium-independent agent prostaglandin F2 alpha was not affected by L-NMMA. We conclude that a metabolite of L-Arg modulates the large coronary artery response to serotonin in vivo.

Animals↗
PubMed2003

Crystal structures of ferrous horse heart myoglobin complexed with nitric oxide and nitrosoethane.

The interactions of nitric oxide (NO) and organic nitroso compounds with heme proteins are biologically important, and adduct formation between NO-containing compounds and myoglobin (Mb) have served as prototypical systems for studies of these interactions. We have prepared crystals of horse heart (hh) MbNO from nitrosylation of aqua-metMb crystals, and we have determined the crystal structure of hh MbNO at a resolution of 1.9 A. The Fe-N-O angle of 147 degrees in hh MbNO is larger than the corresponding 112 degrees angle previously determined from the crystal structure of sperm whale MbNO (Brucker et al., Proteins 1998;30:352-356) but is similar to the 150 degrees angle determined from a MS XAFS study of a frozen solution of hh MbNO (Rich et al., J Am Chem Soc 1998;120:10827-10836). The Fe-N(O) bond length of 2.0 A (this work) is longer than the 1.75 A distance determined from the XAFS study and suggests distal pocket influences on FeNO geometry. The nitrosyl N atom is located 3.0 A from the imidazole N(epsilon) atom of the distal His64 residue, suggesting electrostatic stabilization of the FeNO moiety by His64. The crystal structure of the nitrosoethane adduct of ferrous hh Mb was determined at a resolution of 1.7 A. The nitroso O atom of the EtNO ligand is located 2.7 A from the imidazole N(epsilon) atom of His64, suggesting a hydrogen bond interaction between these groups. To the best of our knowledge, the crystal structure of hh Mb(EtNO) is the first such determination of a nitrosoalkane adduct of a heme protein.

Animals↗
PubMed1991

In-vitro testing and the carcinogenic potential of several nitrosated indole compounds.

4-chloro-methoxyindole is a naturally occurring compound in Vicia faba which can easily react with nitrite to form a N-nitroso compound. In this in vitro study, the potential genotoxic effects of nitrosated 4-chloro-6-methoxyindole and its structural analogue 4-chloroindole were evaluated for the first time by using both Salmonella and Chinese hamster V79 cells. Additionally, the inhibition of gap junctional intercellular communication in V79 cells by these compounds was determined; this is a validated parameter for tumor-promoting activity. Most assays were also performed with nitrosated indole-3-acetonitrile, a naturally occurring compound in brassicas. Both nitrosated chloroindoles were highly mutagenic to Salmonella typhimurium TA100 without the need of exogenous metabolic activation and were potent inducers of Sister Chromatid Exchanges. Nitrosated indole-3-acetonitrile generated the same effects, although at much higher concentrations. Equivocal results were obtained for the nitrosated chloroindoles in a forward mutation assay using the hypoxanthine guaninephosphoribosyltransferase locus. All nitrosated indole compounds significantly inhibited gap junctional intercellular communication. These results indicate that nitrosated chloroindoles and nitrosated indole-3-acetonitrile should be considered as mutagens and agents with potential tumor-promoting capacity.

Animals↗
PubMedDate not supplied

Resistant starches and health.

It was initially hypothesized that resistant starches, i.e., starch that enters the colon, would have protective effects on chronic colonic diseases, including reduction of colon cancer risk and in the treatment of ulcerative colitis. Recent studies have confirmed the ability of resistant starch to increase fecal bulk, increase the molar ratio of butyrate in relation to other short-chain fatty acids, and dilute fecal bile acids. However the ability of resistant starch to reduce luminal concentrations of compounds that are damaging to the colonic mucosa, including fecal ammonia, phenols, and N-nitroso compounds, still requires clear demonstration. As such, the effectiveness of resistant starch in preventing or treating colonic diseases remains to be assessed. Nevertheless, there is a fraction of what has been termed resistant (RS1) starch, which enters the colon and acts as slowly digested or lente carbohydrate in the small intestine. Foods in this class are low glycemic index and have been shown to reduce the risk of chronic disease. They have been associated with systemic physiological effects such as reduced postprandial insulin levels and higher HDL cholesterol levels. Consumption of low glycemic index foods has been shown to be related to reductions in risk of coronary heart disease and Type 2 diabetes. Type 2 diabetes has in turn been related to a higher risk of colon cancer. If carbohydrates have a protective role in colon cancer prevention this may lie partly in the systemic effects of low glycemic index foods. The colonic advantages of different carbohydrates, varying in their glycemic index and resistant starch content, therefore, remain to be determined. However, as recent positive research findings continue to mount, there is reason for optimism over the possible health advantages of those resistant starches, which are slowly digested in the small intestine.

Cardiovascular Diseases↗
PubMed1990

Mutational specificity of alkylating agents and the influence of DNA repair.

Alkylating treatments predominantly induce G: C = greater than A:T transitions, consistent with the predicted significance of the miscoding potential of the O6-alG lesion. However, the frequency and distribution of these events induced by any one compound may be diagnostic. SN1 agents that act via an alkyldiazonium cation, such as the N-nitroso compounds, preferentially generate G: C = greater than A:T transitions at 5'-RG-3' sites, while the more SN2 alkylsulfates and alkylalkane-sulfonates do not. The precise nature of this site bias and the possibility of strand bias are target dependent. The extent of this site bias and the contribution of other base substitutions are substituent size dependent. A similar 5'-RT-3' effect is seen for A:T = greater than G:C transitions, presumably directed by O4-alT lesions. The 5'-RG-3' effect, at least, likely reflects a deposition specificity arising from some aspect of helix geometry, although it may be further exaggerated by alkylation-specific repair. Excision repair appears to preferentially reduce the occurrence of ethylation-induced G:C = greater than A:T and A:T = greater than G:C transitions at sites flanked by A:T base pairs. This may be due to an enhancement of the helical distortion imposed by damage at such positions. A similar effect is not seen for methylation-induced mutations and in the case of propyl adducts, the influence of excision repair on the ultimate distribution of mutation cannot be as easily defined with respect to neighbouring sequence.

Alkylating Agents↗