Concentration Of 8-hydroxydeoxyguanosine Research Articles

Abstract B68: Antioxidant activity of green tea: A phase II clinical trial in men with prostate cancer

Abstract Background: Green tea (GT) contains green tea polyphenols (GTPs) which have been shown to play a role in the regulation of cell proliferation and apoptosis in prostate cancer cells in vitro and in animal models using human prostate cancer cell xenografts. GTPs are also potent scavengers of reactive oxygen species (ROS) which play a role in tumorigenesis. While there is extensive epidemiological and basic science evidence for these effects of GTPs, data from human intervention studies is much more limited. Objective: We conducted a phase II intervention study to evaluate the anticarcinogenic and antioxidant effects of green tea in prostate cancer by administering green tea in men prior to prostatectomy. Design: 79 men, diagnosed with prostate cancer and scheduled for prostatectomy, were randomized to either 6 cups of brewed green tea (GT group, N=34) or water (control group, N=33) daily for 3-8 weeks prior to surgery. 67 men completed the intervention. Blood and urine samples were collected before and after the intervention, and a section of prostate tissue was obtained following the pathology evaluation. Serum prostate specific antigen (PSA) concentration was determined by ELISA assay and prostate tissue PSA protein concentration was measured by Western blot. The prostate concentration of GTPs and their metabolites was measured using high-performance liquid chromatography (HPLC) with CoulArray electrochemical detection. The concentration of 8-hydroxydeoxyguanosine (8-OHdG), a biomarker for oxidative DNA damage, was measured in urine by HPLC. In addition, gene expression of the antioxidant enzymes superoxide dismutase (SOD) and catalase were determined in normal and tumor prostate tissue using real-time quantitative PCR. Results: Statistical analysis within each treatment arm showed that the serum PSA concentration significantly decreased in the GT group (final vs. baseline blood) (P<0.01), while no change was observed in the control group. The comparison of percent change in serum PSA between GT and control group showed a decreasing trend (p=0.085). Prostate tissue PSA protein expression was lower in men consuming GT compared to water control (p=0.06). The major bioactive component of GTPs, epigallocatechin gallate (EGCG) and its methyl metabolite 4″-O-methyl EGCG were found in prostate tissue in similar amounts, along with a small amount of epicatechin gallate. As compared to the pre-intervention level there was a significant decrease in urinary 8-OHdG concentration after GT intervention (83 vs. 50 nmol/g creatinine), while there was no change in the control group (54 vs. 55 nmol/g creatinine). Gene expression of SOD (p=0.087) and catalase (p=0.15) in the prostate tumor tissue normalized to normal prostate tissue in each individual showed a decreasing trend in men consuming GT as compared to the water control. Conclusion: The consumption of 6 cups of GT provided antioxidant protection, which may contribute to an inhibitory effect on prostate tumor growth in humans. Large-scale human intervention studies are needed to confirm these findings. Citation Format: Piwen Wang, William Aronson, Narine Abgaryan, Catherine L. Carpenter, Jaydutt V. Vadgama, David Heber, Susanne M. Henning. Antioxidant activity of green tea: A phase II clinical trial in men with prostate cancer. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B68.

Relationships between periodontal inflammation, lipid peroxide and oxidative damage of multiple organs in rats

Gingival response to periodontal inflammation generates excessive lipid peroxide and such a condition may augment systemic health through increased circulating lipid peroxide. The purpose of the present study was to investigate whether the generation of lipid peroxide in periodontal inflammation could induce tissue injury in the liver, heart, kidney and brain using a rat model. Twelve Wistar rats (8 week-old male) were divided into 2 groups: the periodontal inflammation group, receiving topical application of lipopolysaccharide and proteases to the gingival sulcus for 4 weeks, and the control group using instead pyrogen-free water. After blood samples were collected, specimens from the brain, heart, liver and kidney were resected to determine the concentration of 8-hydroxydeoxyguanosine (an indicator of oxidative DNA damage). Gingival and serum levels for hexanoyl-lysine were measured to evaluate lipid peroxide. Administration of lipopolysaccharide and proteases induced periodontal inflammation, with increasing gingival and serum levels of hexanoyl- lysine. The level of 8-hydroxydeoxyguanosine increased 2.27, 2.01, 1.49 and 1.40 times in mitochondrial DNA from the liver, heart, kidney and brain of rats with periodontal inflammation, respectively. The results reveal that excessive production of lipid peroxide following periodontal inflammation is involved in oxidative DNA damage of the brain, heart, liver and kidney.

Effects of topical application of lipopolysaccharide and proteases on hepatic injury induced by high-cholesterol diet in rats

Topical application of lipopolysaccharide and proteases to the gingival sulcus induced not only periodontal inflammation but also detectable liver changes in rats fed a normal diet. However, these changes in the liver were not sufficient to induce pathological consequences. The purpose of the present study was to investigate whether gingival inflammation-induced liver change would have more dramatic pathological consequences in rats fed a high-cholesterol diet compared with the effect of the high-cholesterol diet alone. Twenty-four male Wistar rats were divided into four groups. During an 8 week experimental period, two groups were fed a normal diet and the other two were fed a high-cholesterol diet containing 1% cholesterol (w/w) and 0.5% cholic acid (w/w). Four weeks prior to the end of the experimental period, one of each of the dietary groups received daily topical application of lipopolysaccharide and proteases to the gingival sulcus, while the other was treated with pyrogen-free water. In the rats without application of lipopolysaccharide and proteases, the serum level of hexanoyl-lysine, scores of steatosis and inflammation, and concentration of 8-hydroxydeoxyguanosine in liver of rats fed a high-cholesterol diet were higher than in those fed a normal diet. In rats fed a high-cholesterol diet, the scores of steatosis and inflammation and the concentration of 8-hydroxydeoxyguanosine in the liver of rats with application of lipopolysaccharide and proteases were higher than in those without. In a rat model, application of lipopolysaccharide and proteases to the gingival sulcus augmented the effect of a high-cholesterol diet on steatosis, inflammation and oxidative damage in the liver.

Chronic Administration of Lipopolysaccharide and Proteases Induces Periodontal Inflammation and Hepatic Steatosis in Rats

Epidemiologic studies suggest a relationship between periodontitis and liver diseases. A rat periodontitis model was used to investigate whether a causal relationship exists between periodontitis and liver diseases. Fourteen male Wistar rats (8 weeks old) were divided into two groups: a periodontitis group in which Escherichia coli lipopolysaccharide (LPS) and Streptomyces griseus proteases were applied into the gingival sulcus for 8 weeks, and a control group using pyrogen-free water instead. After blood samples were collected, periodontal tissues and liver specimens were analyzed. Chronic administration of LPS and proteases to the gingival sulcus induced periodontitis and liver injury, including steatosis with inflammation and sinusoidal fibrosis. Apoptosis, enhanced concentration of 8-hydroxydeoxyguanosine, and activated production of tumor necrosis factor-alpha in liver were observed in the periodontitis group, with increased gingival inflammation, serum LPS, and reactive oxygen species. Periodontal inflammation in a rat model induced fatty liver disease through increased serum LPS.

Suppression of oxidative stress after transient focal ischemia in interleukin-1 knock out mice.

Interleukin-1 (IL-1) contributes to ischemic neurodegeneration. However, the mechanisms regulating action of IL-1 are still poorly understood. In order to clarify this central issue, mice that were gene deficient both IL-1alpha and beta (IL-1 KO) and wild-type mice were subjected to 1 hour transient middle cerebral artery occlusion (tMCAO). The concentration of 8-hydroxy deoxyguanosine (8OHdG) which is considered to be a reliable oxidative DNA damage by superoxide anion, in brain and of total nitric oxide (NO) in plasma were determined by use of HPLC. Twenty-four hours after tMCAO, the ratio of 8OHdG to dG in the ipsilateral hemisphere of wild-type mice were 2.24 x 10(-3) and 4.41 x 10(-3) in the neocortex and striatum, respectively. The concentration of 8OHdG in the ipsilateral hemisphere of the wild-type mice was higher than that of the IL-1 KO mice. The concentration of total NO in the plasma of IL-1 KO mice was also lower than that of the wild-type 24 hours after tMCAO. These results strongly suggest that IL-1 is participated in generating reactive oxygen spices and it aggravates and induces the ischemic neuronal cell death.(183 words).

Health survey on workers and residents near the municipal waste and industrial waste incinerators in Korea.

Hazardous substances, such as polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) also have been detected in Municipal Solid Waste (MSW) and industrial waste incinerators in Korea. In this study, we estimated the exposure status of these hazardous substances and their heath effects in workers and residents near the MSW incinerators and residents near the industrial waste incinerators. We interviewed 13 workers and 16 residents from the area around the two MSW incinerators, and further 10 residents from the area around one industrial waste incinerator, which is suspected to emit higher hazardous substances. During the interview we collected information including sociodemographic information, personal habits, work history, detailed gynecologic and other medical history. Blood samples from 45 subjects were also collected for analysis of PCDDs and PCDFs, which were analyzed by HRGC-HRMS (High Resolution Gas Chromatography-High Resolution Mass Spectrometer). In addition to a questionnaire survey, urinary concentrations of 8-hydroxydeoxyguanosine (8-OH-dG) and malondialdehyde (MDA) were measured as oxidative injury biomarkers. Urinary concentrations of 8-OH-dG were determined by in vitro ELISA (JAICA, Fukuroi, Japan). MDA were determined by HPLC using adduct with TBA (thiobarbituric acid). The PCDD/F concentrations in residents from the area around industrial waste incinerator were higher than those in workers and residents from the area around MSW incinerator. The average toxic equivalency (TEQ) concentrations of PCDD/Fs in residents from the area around industrial waste incinerator were 53.4 pg I-TEQs/g lipid. The average TEQ concentrations of PCDD/Fs in workers and residents near MSW incinerator were 12.2 pg I-TEQs/g lipid. Estimated daily intake (EDI) of each person was calculated, and the EDI of all workers and residents near MSW incinerator were within the tolerable daily intake range. But for only 30% of 10 people near the industrial waste incinerator were the EDI within the tolerable daily intake range (1-4 pg I-TEQ/kg bw/day) suggested by WHO (1997). The oxidative stress of residents near the industrial waste incinerator was higher than that in workers and residents from the area around MSW incinerator. This oxidative stress may have been caused by hazardous substances, such as PCDD/Fs emitted by incinerators. The residents from the area around industrial waste incinerator were exposed to hazardous substances such as PCDD/ Fs. Proper protection strategies against these hazardous chemicals are needed.

Genetic susceptibility of term pregnant women to oxidative damage

Genetic polymorphisms involved in the activation and detoxification of exogenous chemicals and in the production and scavenging of reactive oxygen species may modulate the levels of oxidative injury biomarker. We investigated 81 pregnant women in Inchon, Korea. In addition to a questionnaire survey, urinary concentrations of 8-hydroxydeoxyguanosine (8-OH-dG) and malondialdehyde (MDA) were measured as oxidative injury biomarkers. Cytochrome P-450( CYP) 1A1, CYP2E1, glutathione S-transferase ( GST) M1 and GSTT1 polymorphisms and myeloperoxidase ( MPO) and manganese superoxide dismutase ( MnSOD) polymorphisms were evaluated to determine the effect of genetic modification on urinary 8-OH-dG and MDA. The concentrations of urinary 8-OH-dG were significantly elevated in the presence of the MnSOD variant genotype ( P=0.04) and in the case of GSTM1 null status ( P=0.02) by multivariate regression. The concentrations of urinary MDA were not affected significantly by the genetic polymorphisms. This result shows that oxidative stress injury is modified by some heritable polymorphisms, including GSTM1 and MnSOD.

Autoxidation and toxicant-induced oxidation of lipid and DNA in monkey liver: reduction of molecular damage by melatonin.

Melatonin, the main secretory product of the pineal gland, is a free radical scavenger and antioxidant which protects against oxidative damage due to a variety of toxicants. However, there is little information regarding melatonin's antioxidative capacity in tissues of primates. In this study we examined the protective effects of melatonin in monkey liver homogenates against lipid damage that occurred as a result of autoxidation or that induced by exogenous addition of H202 and ferrous iron (Fe2+). Additionally, we tested melatonin's protective effect against oxidative damage to DNA induced by chromium(III) (CrIII) plus H202. The levels of malondialdehyde and 4-hydroxyalkenals were assayed as an index of lipid peroxidation, and the concentrations of 8-hydroxydeoxyguanosine (8-OHdG) as an endpoint of oxidative DNA damage. The increases in malondialdehyde+4-hydroxyalkenals concentrations as a consequence of autoxidation or after the addition of H202 plus Fe2+ to the homogenates were time-dependent. The accumulation of these damaged products due to either auto-oxidative processes or induced by H202 and Fe2+ were significantly reduced by melatonin in a concentration-dependent-manner. The levels of 8-OHdG were elevated in purified monkey liver DNA incubated with a combination of CrCl3 plus H2O2. This rise in oxidatively damaged DNA was prevented by 10 microM concentration of melatonin. Also, melatonin reduced the damage to DNA that was caused by auto-oxidative processes. These findings in monkey liver tissue document the ability of melatonin to protect against oxidative damage to both lipid and DNA in primate tissue, as observed previously in rodent tissue. The findings provide support for the use of melatonin as suitable agent to reduce damage inflicted by free radical species in primates.

Autoxidation and Toxicant‐Induced Oxidation of Lipid and DNA in Monkey Liver: Reduction of Molecular Damage by Melatonin

Abstract: Melatonin, the main secretory product of the pineal gland, is a free radical scavenger and antioxidant which protects against oxidative damage due to a variety of toxicants. However, there is little information regarding melatonin's antioxidative capacity in tissues of primates. In this study we examined the protective effects of melatonin in monkey liver homogenates against lipid damage that occurred as a result of autoxidation or that induced by exogenous addition of H2O2 and ferrous iron (Fe2+). Additionally, we tested melatonin's protective effect against oxidative damage to DNA induced by chromium(III) (CrIII) plus H2O2. The levels of malondialdehyde and 4‐hydroxyalkenals were assayed as an index of lipid peroxidation, and the concentrations of 8‐hydroxydeoxyguanosine (8‐OHdG) as an endpoint of oxidative DNA damage. The increases in malondialdehyde+4‐hydroxyalkenals concentrations as a consequence of autoxidation or after the addition of H2O2 plus Fe2+ to the homogenates were time‐dependent. The accumulation of these damaged products due to either autoxidative processes or induced by H2O2 and Fe2+ were significantly reduced by melatonin in a concentration‐dependent‐manner. The levels of 8‐OHdG were elevated in purified monkey liver DNA incubated with a combination of CrCl3 plus H2O2. This rise in oxidatively damaged DNA was prevented by 10 μM concentration of melatonin. Also, melatonin reduced the damage to DNA that was caused by autoxidative processes. These findings in monkey liver tissue document the ability of melatonin to protect against oxidative damage to both lipid and DNA in primate tissue, as observed previously in rodent tissue. The findings provide support for the use of melatonin as suitable agent to reduce damage inflicted by free radical species in primates.

Exposure to Indoor Background Radiation and Urinary Concentrations of 8-Hydroxydeoxyguanosine, a Marker of Oxidative DNA Damage

We investigated whether exposure to indoor [gamma]-radiation and radon might be associated with enough free radical formation to increase urinary concentrations of 8-hydroxydeoxyguanosine (8-OHdG), a sensitive marker of DNA damage, due to a hydroxyl radical attack at the C8 of guanine. Indoor radon and [gamma]-radiation levels were measured in 32 dwellings for 6 months by solid-state nuclear track detectors and thermoluminescent dosimeters, respectively. Urine samples for 8-OHdG determinations were obtained from 63 healthy adult subjects living in the measured dwellings. An overall tendency toward increasing levels of 8-OHdG with increasing levels of radon and [gamma]-radiation was seen in the females, presumably due to their estimated longer occupancy in the dwellings measured. Different models were considered for females, with the steepest slopes obtained for [gamma]-radiation with a coefficient of 0.500 (log nmol/l of 8-OHdG for each unit increase of [gamma]-radiation on a log scale) (p<0.01), and increasing to 0.632 (p = 0.035), but with larger variance, when radon was included in the model. In conclusion, there seems to be an effect of indoor radioactivity on the urinary excretion of 8-OHdG for females, who are estimated to have a higher occupancy in the dwellings measured than for males, for whom occupational and other agents may also influence 8-OHdG excretion. ree radicals; [gamma]-radiation; radon.

Exposure to indoor background radiation and urinary concentrations of 8-hydroxydeoxyguanosine, a marker of oxidative DNA damage.

We investigated whether exposure to indoor [gamma]-radiation and radon might be associated with enough free radical formation to increase urinary concentrations of 8-hydroxydeoxyguanosine (8-OHdG), a sensitive marker of DNA damage, due to a hydroxyl radical attack at the C8 of guanine. Indoor radon and [gamma]-radiation levels were measured in 32 dwellings for 6 months by solid-state nuclear track detectors and thermoluminescent dosimeters, respectively. Urine samples for 8-OHdG determinations were obtained from 63 healthy adult subjects living in the measured dwellings. An overall tendency toward increasing levels of 8-OHdG with increasing levels of radon and [gamma]-radiation was seen in the females, presumably due to their estimated longer occupancy in the dwellings measured. Different models were considered for females, with the steepest slopes obtained for [gamma]-radiation with a coefficient of 0.500 (log nmol/l of 8-OHdG for each unit increase of [gamma]-radiation on a log scale) (p<0.01), and increasing to 0.632 (p = 0.035), but with larger variance, when radon was included in the model. In conclusion, there seems to be an effect of indoor radioactivity on the urinary excretion of 8-OHdG for females, who are estimated to have a higher occupancy in the dwellings measured than for males, for whom occupational and other agents may also influence 8-OHdG excretion. ree radicals; [gamma]-radiation; radon.

Oxidative DNA damage accumulation in gastric carcinogenesis

Background—Gastric carcinogenesis is a multifactorial, multistep process, in which chronic inflammation plays a major role.Aims—In order to ascertain whether free radical mediated oxidative DNA damage is involved in such a...

SHORT COMMUNICATION: Glutathione modulates the formation of 8-hydroxydeoxyguannosine in isolated DNA and mutagenicity in Salmonella typhimurium TA100 induced by mineral fibres

Treatment of isolated DNA with crocidolite and man-made vitreous fibre-21 (MMVF-21) significantly increased the concentration of 8-hydroxydeoxyguanosine (8-OHdG) in isolated DNA above background levels and co-treatment with glutathione (GSH) eliminated this effect. Crocidolite, MMVF-21 and chrysotile fibres increased the number of revertants in Salmonella typhimurium TA100 and GSH-deficient strains, TA100/NG-54 and TA100/NG-57, over background levels. This increase was small in TA100 but was greater in the GSH-deficient strains. When these bacterial strains were further depleted of GSH by co-culture with buthionine sulfoximine, all fibres tested caused a significant increase in the number of revertants over the parent strains. Pre-treatment with the GSH precursor N-acetyl-L-cysteine reduced the number of revertants to below that of the parent strain. Previous studies have shown a mechanistic role for iron-catalyzed production of oxygen radicals in the mutagenicity of fibres and this study suggests a protective role for GSH against such oxidative damage possibly by acting as a radical scavenger.

Oxidative stress and aging in the Mongolian gerbil ( Meriones unguiculatus)

The objective of this study was to determine if aging in the gerbil, Meriones unguiculatus, is associated with elevation in the level of oxidative stress. Studies were conducted on the brain, heart, kidney, liver and testis of young (3–6 months), adult (15 months), and old (23–25 months) animals. Oxidative damage to proteins, measured as the concentration of protein carbonyls and loss of activity of glucose-6-phosphate dehydrogenase, and to DNA, measured as the concentration of 8-hydroxydeoxyguanosine, increased with age of the animals. There was no appreciable age-related change in the activity of alkaline proteases, which preferentially degrade oxidized protein. Rates of mitochondrial superoxide anion radical and hydrogen peroxide generation also increased with age, most notably in the heart. Antioxidative defenses, measured as activities of superoxide dismutase, catalase and glutathione peroxidase and concentration of glutathione, did not exhibit a uniform pattern of age-related changes. However, when the antioxidative potential of the tissue homogenates was measured as their susceptibility to undergo protein oxidation, in response to experimentally-induced oxidative stress, using X-irradiation, tissues of the old animals were significantly more vulnerable than those of the young animals. Results of this study are interpreted to indicate: (i) that the level of molecular oxidative damage to DNA and proteins increases with age, and (ii) that the increased oxidative damage is due to both an elevation in the rates of oxidant generation and an increase in the susceptibility of tissues to oxidative damage.

DNA oxidative damage and life expectancy in houseflies.

The objective of this study was to explore the relationship between oxidative molecular damage and the aging process by determining whether such damage is associated with the rate of aging, using the adult housefly as the experimental organism. Because the somatic tissues in the housefly consist of long-lived postmitotic cells, it provides an excellent model system for studying cumulative age-related cellular alterations. Rate of aging in the housefly was manipulated by varying the rate of metabolism (physical activity). The concentration of 8-hydroxydeoxyguanosine (80HdG) was used as an indicator of DNA oxidation. Exposure of live flies to x-rays and hyperoxia elevated the level of 8OHdG. The level of 8OHdG in mitochondrial as well as total DNA increased with the age of flies. Mitochondrial DNA was 3 times more susceptible to age-related oxidative damage than nuclear DNA. A decrease in the level of physical activity of the flies was found to prolong the life-span and corresponding reduce the level of 8OHdG in both mitochondrial and total DNA. Under all conditions examined, mitochondrial DNA exhibited a higher level of oxidative damage than total DNA. The 8OHdG levels were found to be inversely associated with the life expectancy of houseflies. The pattern of age-associated accrural of 8OHdG was virtually identical to that of protein carbonyl content. Altoghether, results of this study support the hypothesis that oxidative molecular damage is a causal factor in senescence.

Exposure to benzene and urinary concentrations of 8-hydroxydeoxyguanosine, a biological marker of oxidative damage to DNA.

Benzene is an established animal and human carcinogen. The mechanism of benzene toxicity, particularly its leukaemogenic effect, is not fully understood. The modified base 8-hydroxy-deoxyguanosine (8-OHdG) is a sensitive marker of the DNA damage due to hydroxyl radical attack at the C8 of guanine. This damage, if left unrepaired, has been proposed to contribute to mutagenicity and cancer promotion. We conducted this biomonitoring study with the aim of evaluating the association between excretion of 8-OHdG and level of exposure to benzene and other aromatic compounds among occupationally exposed people. A random sample of 65 filling station attendants from Rome, Italy was studied for personal exposure to benzene, toluene, and xylenes, and excretion of 8-OHdG. Information about age, length of employment, smoking habits, and diagnostic exposure to x rays was collected by questionnaire. An average yearly level of exposure to benzene and methylbenzenes was calculated for each filling station attendant on the basis of about seven repeated personal samples collected during one year. A spot sample of 20 ml of urine was collected from each worker. Concentrations of 8-OHdG were determined by high performance liquid chromatography (HPLC) with coupled columns. A mean (SD) concentration of 1.36 (0.49) mumol of 8-OHdG/mol of creatinine was measured. A significant correlation was found between urinary 8-OHdG and exposure to benzene (r = 0.34). In a multiple regression analysis relating the concentration of urinary 8-OHdG with the age, length of employment, smoking, diagnostic exposure to x rays and personal exposure to benzene, an increase of 0.15 mumol/mol creatinine in urinary 8-OHdG/unit increase in the natural logarithm of the average yearly benzene concentration was estimated. This study shows a dose-response effect between personal exposure to benzene and urinary 8-OHdG concentration; further studies are needed to clarify the biological significance of 8-OHdG as a marker of cancer risk.

Effect of age and caloric restriction on DNA oxidative damage in different tissues of C57BL/6 mice

The objective of this study was to explore the role of molecular oxidative damage and caloric intake in the aging process. The concentration of 8-hydroxydeoxyguanosine (8-OHdG), a product of DNA oxidation, was compared in five different tissues of mice (skeletal muscle, brain, heart, liver and kidney) as a function of age and in response to dietary restriction. A comparison of 8- and 27-month-old mice indicated that the age-related increase in 8-OHdG concentration was greater in skeletal muscle, brain and heart, which are primarily composed of long-lived, post-mitotic cells, than in liver and kidney, which consist of slow-dividing cells. Dietary restricted (DR) mice kept on 60% caloric intake as compared to the ad libitum-fed (AL) mice showed a lower concentration in 8-OHdG content in all the tissues compared to AL mice. The DR-related amelioration of DNA oxidative damage was greater in the post-mitotic tissues compared to those undergoing slow mitoses. Results support the hypothesis that oxidative damage to long-lived post-mitotic cells may be a key factor in the aging process.

Iron-dependent formation of 8-hydroxydeoxyguanosine in isolated DNA and mutagenicity in Salmonella typhimurium TA102 induced by crocidolite.

Treatment of isolated DNA with crocidolite asbestos significantly increased the concentration of 8-hydroxydeoxyguanosine (8-OHdG) above background. Furthermore, incubating DNA with H2O2 and crocidolite potentiated the formation of 8-OHdG above levels observed with crocidolite alone. In the presence of desferrioxamine, desferrioxamine and ferrozine, dimethylsulphoxide (DMSO) or o-phenanthroline, crocidolite-induced DNA oxidation was reduced by 36, 73, 74 and 70% respectively. Crocidolite, but not chrysotile asbestos, enhanced background revertants in Salmonella typhimurium TA102, at sub-cytotoxic concentrations in a dose-dependent manner. The mutagenic effects of crocidolite were quite small and this indicates that crocidolite was a weak mutagen in this study. The number of revertants was reduced to the spontaneous rate for this strain after the fibres had been pretreated with desferrioxamine before assaying for genotoxicity in this oxygen radical-sensitive strain. These results help to explain a mechanistic role for iron in crocidolite-induced DNA oxidation and mutagenicity in TA102.

Production of 8-hydroxydeoxyguanosine in isolated DNA by chromium(VI) and chromium(V).

Chromium(VI) and Cr(V) compounds increased the concentration of 8-hydroxydeoxyguanosine (oh8dG) in isolated DNA, whereas no such increase was seen with Cr(III). Furthermore, incubating DNA with H2O2 and Cr(VI) or Cr(V) potentiated the formation of oh8dG above levels observed with either chromium compound alone. In the presence of catalase, the increase in DNA oxidation observed with Cr(VI) was inhibited, the base oxidation observed being equivalent to background levels, and this indicated involvement of H2O2 in the mechanism. Glutathione did not enhance chromium-induced formation of this oxidized base. These results help to explain a mechanism of chromium-induced DNA oxidation involving H2O2 via a Fenton-type reaction.