DNA Damage In Liver Of Rats Research Articles

Mitochondrial dysfunction and oxidative stress in liver of male albino rats after exposing to sub-chronic intoxication of chlorpyrifos, cypermethrin, and imidacloprid

The adverse effects of chlorpyrifos, cypermethrin, and imidacloprid on mitochondrial dysfunction and oxidative stress biomarkers were studied in rat liver. The liver deficiency was also confirmed by histological analysis and gel electrophoresis. Each insecticide was administered orally with five doses per week for 28 days to male albino rats at 1/50 of the LD50 per insecticide. The results demonstrated that the mitochondrial dysfunction was confirmed by a significant decrease in NADH dehydrogenase and ATPase activities. Oxidative stress biomarkers include malondialdehyde (MDA), and protein carbonyl content (PCC) were significantly increased. However, superoxide dismutase (SOD) and glutathione S-transferase (GST) as antioxidant enzymes were significantly decreased in the mitochondria of the rat liver. HPLC analysis showed a significant increase of the 8-hydroxy-2′-deoxyguanosine (8-OH-2DG) as a biomarker of the DNA damage in rat liver. In addition, the residue levels of 0.96 and 0.29 μg/mL serum were found for cypermethrin and imidacloprid, respectively. However, chlorpyrifos not detected using the HPLC analysis. Blue native polyacrylamide gel electrophoresis (BN-PAGE) analysis showed a change in the pattern and sequence of complexions of the electron transport chain in liver mitochondria with treatment by such insecticides. The hepatic histological examination also showed symptoms of abnormalities after exposure to these insecticides.

Effects of selenium status on Aroclor 1254-induced DNA damage in rat liver and kidney

Effects of selenium status on Aroclor 1254-induced DNA damage in rat liver and kidney

Sex-specific dose-response analysis of genotoxicity in cyproterone acetate-treated F344 rats

Cyproterone acetate (CPA), a synthetic hormonal drug, induces rat liver tumors in a sex-specific manner, with five-fold higher doses needed to induce liver tumors in male rats compared to females. In order to evaluate the potential of the in vivo alkaline Comet assay to predict the sex-specific carcinogenicity of CPA, CPA-induced direct DNA damage (DNA strand breaks and alkali-labile sites) were evaluated in the livers of both male and female F344 rats. In addition, secondary oxidative DNA damage was measured concurrently utilizing the human 8-oxoguanine-DNA-N-glycosylase (hOGG1) and EndonucleaseIII (EndoIII)-modified in vivo alkaline Comet assays and the reticulocyte micronucleus (MN) frequency was analyzed in peripheral blood. Groups of 5 seven-week-old male and female F344 rats received olive oil or 10, 25, 50 or 100mg/kg bw CPA in olive oil by gavage at 0, 24, and 45h and were sacrificed at 48h. CPA-induced direct DNA damage in rat liver showed the same sex-specific pattern as its hepatotumorigenicity: a five-fold-higher dose of CPA was needed to induce a statistically significant increase in direct DNA damage in livers of males compared to females. However, peripheral blood MN frequency was weak in both sexes and CPA-induced oxidative DNA damage was generally greater in male than female rat livers. Taken together, our results demonstrate concordance in the sex-specificity of CPA in the in vivo alkaline Comet assay and cancer bioassay, while the induction of oxidative DNA damage by CPA was not directly correlated with its tumorigenicity.

D-phenothrin-induced oxidative DNA damage in rat liver and kidney determined by HPLC-ECD/DAD

The objective of this study was to assess the risk of genotoxicity of d-phenothrin by measuring the oxidative stress it causes in rat liver and kidney. The level of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG)/10(6) 2'-deoxyguanosine (dG) was measured by using high performance liquid chromatography (HPLC) with a diode array (DAD) and an electrochemical detector (ECD). Sixty male Wistar albino rats were randomly divided into five experimental groups and one control group of 10 rats/group. d-phenothrin was administered intraperitoneally (IP) to the five experimental groups at 25 mg/kg (Group I), 50 mg/kg (Group II), 66.7 mg/kg (Group III), 100 mg/kg (Group IV), and 200 mg/kg (Group V) for 14 consecutive days, and the control group received only the vehicle, dimethyl sulfoxide (DMSO). DNA from samples frozen in liquid nitrogen was isolated with a DNA isolation kit. Following digestion with nuclease P1 and alkaline phosphatase (ALP), hydrolyzed DNA was subjected to HPLC. The dG and 8-oxodG levels were analyzed with a DAD and ECD, respectively. In the experimental groups, the mean 8-oxodG/10(6) dG levels were 48.15 ± 7.43, 68.92 ± 20.66, 82.07 ± 14.15, 85.08 ± 28.50, and 89.14 ± 21.73 in livers and 39.06 ± 7.63, 59.69 ± 14.22, 61.13 ± 17.46, 65.13 ± 23.40, and 72.66 ± 19.04 in kidneys of Groups I, II, III, IV, and V, respectively. The mean 8-oxodG/10(6) dG levels in the control groups were 44.96 ± 12.66 for the liver and 39.07 ± 4.80 for the kidney. A statistically significant (p < 0.05), dose-dependent increase in oxidative DNA damage was observed in both organs of animals exposed to d-phenothrin when compared to controls. Furthermore, the liver showed a significantly higher level of oxidative DNA damage than the kidney (p < 0.01). In conclusion, d-phenothrin administered to rats intraperitoneally for 14 consecutive days generated free radical species in a dose-dependent manner and caused oxidative DNA damage in the liver and kidney.

Propolis alleviates 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced histological changes, oxidative stress and DNA damage in rat liver

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces hepatic damage. Propolis exhibits antioxidant properties and several studies suggest that supplementations with antioxidants can influence hepatotoxicity. Therefore, the aim of the current study was to explore the effectiveness of propolis in alleviating the toxicity of TCDD in the liver of rats. Animals were divided into six groups, namely, TCDD (0.75 and 8µg/kgbody weight (bw)), propolis (50mg/kgbw), TCDD (0.75 and 8µg) plus propolis (50mg/kg bw), and control, respectively. Rats were intraperitoneally administered with their respective doses daily for 21 days. In rats that received a high dose of TCDD, the antioxidant enzymes were significantly decreased and the serious pathological findings were established. Also, the rate of hepatocyte micronucleus (HMN) was increased after treating with TCDD. The reactions of enzymes in control and low-dose group were weak. The frequencies of HMN and liver histology were similar to both the groups. The presence of propolis with TCDD alleviated its pathological effects in hepatic tissue. Propolis also prevented the suppression of antioxidant enzymes in the livers of animals exposed to TCDD and displayed a strong protective effect against HMN. It can be concluded that propolis has beneficial influences and was able to antagonize TCDD toxicity in the liver.

Ameliorative effect of docosahexaenoic acid on 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced histological changes, oxidative stress, and DNA damage in rat liver

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant that leads to the development of hepatotoxicity. Docosahexaenoic acid (DHA) has been proposed to counteract oxidative stress and improve antioxidant status, and several studies suggest that supplementations with antioxidants can influence hepatotoxicity. The aim of the current study was to explore the role of DHA in modulating the toxicity of TCDD in the liver of Sprague-Dawley rats. Animals were assigned to four groups (n = 5): control (only dimethyl sulfoxide (DMSO)), 8 μg/kg body weight (b.w.) TCDD in DMSO solution; 250 mg/kg b.w. DHA and TCDD plus DHA; respectively. Rats were intraperitoneally administered their respective doses daily for 21 days. On day 21, the animals were killed, and then biochemical tests, pathological examination, and micronucleus (MN) assay were performed in the liver. Our results showed that the activities of antioxidant enzymes were significantly decreased and serious pathological findings were established in rats that received TCDD. Beside the rate of MNs in hepatocytes was increased after the treatment with dioxin. In rats treated with DHA alone, MNs were not changed and the activities of antioxidant enzymes were significantly increased. The presence of DHA with TCDD alleviated its pathological effects in hepatic tissue. DHA also prevented the suppression of antioxidant enzymes in the livers of animals exposed to TCDD and displayed a strong protective effect against MNs. It can be concluded that DHA has beneficial influences and could be able to antagonize TCDD toxicity in liver.

Methyleugenol Genotoxicity in the Fischer 344 Rat Using the Comet Assay and Pathway-Focused Gene Expression Profiling

Methyleugenol (MEG), a constituent of human food, induces malignant tumors in multiple tissues of rats and mice. Although MEG forms DNA adducts and induces unscheduled DNA synthesis in rat liver, it is negative in many in vitro genetic toxicity assays. In the present study, we evaluated MEG-induced DNA damage in the rat using (1) the alkaline Comet assay, (2) the oxidative Comet assay, and (3) expression profiling of genes associated with DNA damage pathways. Male F344 rats received single oral doses of 400 or 1000 mg/kg body weight (bw) MEG and DNA damage was assessed by the Comet assay in liver, bladder, bone marrow, kidney, and lung 3 h and 24 h later. MEG failed to produce any increase in DNA damage. In addition, rats were given a single oral dose of 2000 mg/kg bw MEG, and Comet assays were performed with liver, bone marrow, and bladder 1, 3, 6, and 8 h later. With one exception (bone marrow at 8 h), no DNA damage was detected. Enzyme-modified Comet assays were conducted in parallel with standard Comet assays in liver. Whereas no MEG-induced DNA damage was detected following formamidopyrimidine DNA glycosylase digestion, digestion with endonuclease III resulted in increases in DNA damage at the 6- and 8-h sampling times. Gene expression analysis on the livers from MEG-exposed rats showed significant reduction in genes associated with DNA repair. The results indicate that MEG induces DNA damage in rat liver and that oxidative DNA damages may be partly responsible for the genotoxicity of MEG in rodents.

Low Doses of the Carcinogen Furan Alter Cell Cycle and Apoptosis Gene Expression in Rat Liver Independent of DNA Methylation

BackgroundEvidence of potent rodent carcinogenicity via an unclear mechanism suggests that furan in various foods [leading to an intake of up to 3.5 μg/kg body weight (bw)/day] may present a potential risk to human health.ObjectivesWe tested the hypothesis that altered expression of genes related to cell cycle control, apoptosis, and DNA damage may contribute to the carcinogenicity of furan in rodents. In addition, we investigated the reversibility of such changes and the potential role of epigenetic mechanisms in response to furan doses that approach the maximum estimated dietary intake in humans.MethodsThe mRNA expression profiles of genes related to cell cycle, apoptosis, and DNA damage in rat liver treated with furan concentrations of 0.1 and 2 mg/kg bw were measured by quantitative polymerase chain reaction (PCR) arrays. We assessed epigenetic changes by analysis of global and gene-specific DNA methylation [methylation-specific PCR, combined bisulfite restriction analysis (COBRA), and methylated DNA immunoprecipitation chip] and microRNA (miRNA) analyses.ResultsThe expression profiles of apoptosis-related and cell-cycle–related genes were unchanged after 5 days of treatment, although we observed a statistically significant change in the expression of genes related to cell cycle control and apoptosis, but not DNA damage, after 4 weeks of treatment. These changes were reversed after an off-dose period of 2 weeks. None of the gene expression changes was associated with a change in DNA methylation, although we detected minor changes in the miRNA expression profile (5 miRNA alterations out of 349 measured) that may have contributed to modification of gene expression in some cases.ConclusionNongenotoxic changes in gene expression may contribute to the carcinogenicity of furan in rodents. These findings highlight the need for a more comprehensive risk assessment of furan exposure in humans.

Effect of methionine dietary supplementation on mitochondrial oxygen radical generation and oxidative DNA damage in rat liver and heart

Methionine restriction without energy restriction increases, like caloric restriction, maximum longevity in rodents. Previous studies have shown that methionine restriction strongly decreases mitochondrial reactive oxygen species (ROS) production and oxidative damage to mitochondrial DNA, lowers membrane unsaturation, and decreases five different markers of protein oxidation in rat heart and liver mitochondria. It is unknown whether methionine supplementation in the diet can induce opposite changes, which is also interesting because excessive dietary methionine is hepatotoxic and induces cardiovascular alterations. Because the detailed mechanisms of methionine-related hepatotoxicity and cardiovascular toxicity are poorly understood and today many Western human populations consume levels of dietary protein (and thus, methionine) 2-3.3 fold higher than the average adult requirement, in the present experiment we analyze the effect of a methionine supplemented diet on mitochondrial ROS production and oxidative damage in the rat liver and heart mitochondria. In this investigation male Wistar rats were fed either a L-methionine-supplemented (2.5 g/100 g) diet without changing any other dietary components or a control (0.86 g/100 g) diet for 7 weeks. It was found that methionine supplementation increased mitochondrial ROS generation and percent free radical leak in rat liver mitochondria but not in rat heart. In agreement with these data oxidative damage to mitochondrial DNA increased only in rat liver, but no changes were observed in five different markers of protein oxidation in both organs. The content of mitochondrial respiratory chain complexes and AIF (apoptosis inducing factor) did not change after the dietary supplementation while fatty acid unsaturation decreased. Methionine, S-AdenosylMethionine and S-AdenosylHomocysteine concentration increased in both organs in the supplemented group. These results show that methionine supplementation in the diet specifically increases mitochondrial ROS production and mitochondrial DNA oxidative damage in rat liver mitochondria offering a plausible mechanism for its hepatotoxicity.

Effect of Chokeberry (Aronia melanocarpa) Juice on the Metabolic Activation and Detoxication of Carcinogenic N-Nitrosodiethylamine in Rat Liver

Chokeberry is a rich source of polyphenols, which may counteract the action of chemical carcinogens. The aim of this study was to examine the effect of chokeberry juice alone or in combination with N-nitrosodiethylamine (NDEA) on phase I and phase II enzymes and DNA damage in rat liver. The forced feeding with chokeberry juice alone decreased the activities of enzymatic markers of cytochrome P450, CYP1A1 and 1A2. NDEA treatment also decreased the activity of CYP2E1 but enhanced the activity of CYP2B. Pretreatment with chokeberry juice further reduced the activity of these enzymes. Modulation of P450 enzyme activities was accompanied by the changes in the relevant proteins levels. Phase II enzymes were increased in all groups of animals tested. Chokeberry juice augmented DNA damage and aggravated the effect of NDEA. These results indicate that chokeberry may protect against liver damage; however, in combination with chemical carcinogens it might enhance their effect.

Chlorpyrifos‐induced DNA damage in rat liver and brain

Chlorpyrifos (O,O'-diethyl-O-3,5,6-trichloro-2-pyridyl phosphorothionate, CPF) is a broad spectrum organophosphate pesticide used to control a variety of pests. The present study was undertaken to test the in vivo genotoxic potential of CPF in rats, using the single cell gel electrophoresis (or comet) assay. The rats were administered 50 mg and 100 mg CPF/kg body weight daily for 1, 2, and 3 days as well as 1.12 mg and 2.24 mg CPF/kg body weight for 90 days. The level of DNA damage was estimated by scoring 100 cells per animal, dividing into five types: types 0, I, II, III, and IV. The results clearly indicate that exposure to CPF, acutely or chronically, caused a dose-dependent increase in DNA damage in the liver and brain of rats. From the present study, it can be concluded that CPF exhibits genotoxic potential in vivo.

Inhibition of Carcinogen-Induced DNA Damage in Rat Liver and Colon by Garlic Powders With Varying Alliin Content

: The present study was designed to investigate the protective efficiency of three garlic powders, obtained from bulbs grown in soils with different levels of sulfur fertilization, against DNA damage. Increasing fertilization of soil resulted in an increased alliin content of the powders. Garlic powders were administered to rats for 2 weeks (5% of the diet) and their antigenotoxic effects were examined in the liver and the colon using the comet assay. Consumption of the different garlic powders induced a 35–60% reduction in DNA damage induced by N-nitrosodimethylamine (NDMA) in rat liver. Increased alliin content of the garlic powder was associated strongly with a proportional decrease in NDMA induced DNA alteration. DNA damage induced by aflatoxin B1 in the liver or by 1,2-dimethylhydrazine in the colon were also decreased strongly by the three garlic powders but these decreases were not correlated to the alliin content of the garlic powders. Feeding garlic powders did not modify the genotoxic activity of the direct-acting carcinogen methylnitrosourea in the colon. Part of our results supports evidence that fertilization can have an impact on the protective capacity of garlic bulbs.

Protein Restriction Without Strong Caloric Restriction Decreases Mitochondrial Oxygen Radical Production and Oxidative DNA Damage in Rat Liver

Previous studies have shown that caloric restriction decreases mitochondrial oxygen radical production and oxidative DNA damage in rat organs, which can be linked to the slowing of aging rate induced by this regime. These two characteristics are also typical of long-lived animals. However, it has never been investigated if those decreases are linked to the decrease in the intake of calories themselves or to decreases in specific dietary components. In this study the possible role of the dietary protein was investigated. Using semipurified diets, the ingestion of proteins of Wistar rats was decreased by 40% below that of controls while the other dietary components were ingested at the same level as in animals fed ad libitum. After seven weeks in this regime the liver of the protein restricted animals showed 30-40% decreases in mitochondrial production of reactive oxygen species (ROS) and in oxidative damage to nuclear and mitochondrial DNA. The decreases in ROS generation occurred specifically at complex I. They also occurred without changes in mitochondrial oxygen consumption. Instead, there was a decrease in the percent free radical leak (the percentage of total electron flow leading to ROS generation in the respiratory chain). These results are strikingly similar to those previously obtained after 40% caloric restriction in the liver of Wistar rats. Thus, the results suggest that part of the decrease in aging rate induced by caloric restriction can be due to the decreased intake of proteins acting through decreases in mitochondrial ROS production and oxidative DNA damage. Interestingly, these tissue oxidative stress-linked parameters can be lowered by restricting only the intake of dietary protein, probably a more feasible option than caloric restriction for adult humans.

High Dietary Intake of Sodium SeleniteInduces Oxidative DNA Damage in Rat Liver

One mechanism for the cancer-chemopreventive effects of high selenium (Se) intake is hypothesized to be antioxidant protection of DNA. In this work we examine DNA oxidation in whole animals as a function of dietary Se intake and carcinogen administration. Weanling male Sprague-Dawley rats were fed a basal, Torula yeast-based, Se-deficient diet supplemented with 0, 0.15, or 2.0 ppm Se as sodium selenite for 10 wk. They were then injected with 0, 0.1, or 10 mg /kg body weight of the pro-oxidant carcinogen N-nitrosodiethylamine. High levels of carcinogen and high levels of selenite intake each increased concentration of 8-hydroxy-2'-deoxyguanosine in liver DNA. Se-dependent glutathione peroxidase I gene expression and enzyme activity were dramatically reduced by dietary Se deficiency but were unaffected by carcinogen administration. There were no significant main or interactive effects of Se or carcinogen on activity or gene expression of the DNA repair enzyme 8-oxoguanine glycosylase I. These results do not support the hypothesis that high Se intake may be cancer-preventive by inhibiting oxidative DNA damage. Rather than inhibiting oxidative DNA damage, these findings suggest that high dietary intake of inorganic Se may promote in vivo DNA oxidation.

Oxidative stress and DNA damage in Fischer rats following acute exposure to trichloroethylene or perchloroethylene

Oxidative DNA damage is emerging as an biomarker of effect in studies assessing the health risks of occupational chemicals. Trichloroethylene (TCE) and perchloroethylene (PERC) are used in the dry cleaning industry and their metabolism can produce reactive oxygen compounds. The present study examined the potential for TCE and PERC to induce oxidative DNA damage in rats that was detectable as increased urinary excretion of 8-hydroxydeoxyguanosine (8OHdG). Thiobarbaturic acid reactive substances (TBARS) and 8-epi-prostaglandin F 2α (8epiPGF) were also measured as biomarkers of increased oxidative stress. Male Fischer rats were administered a single i.p. injection of 0, 100, 500, or 1000 mg/kg of PERC or TCE. Control rats received only vehicle (1:4 v/v of Alkamuls/water). A positive control group received 100 mg/kg 2-nitropropane (2NP). Rats were sacrificed 24 h after dosing. In rats receiving 2NP or TCE but not PERC, TBARS and the 8OHdG/dG ratios were significantly elevated in liver. Lymphocyte 8OHdG/dG was not affected significantly by 2NP, TCE or PERC. In rats receiving 2NP, urinary excretion of 8OHdG and 8epiPGF2 were significantly increased. In rats receiving TCE or PERC, significant increases in 8epiPGF2 or 8OHdG were not evident. Results indicate that a single high dose of TCE, but not PERC, can induce an increase in oxidative DNA damage in rat liver. However, the usefulness of 8OHdG as a biomarker of TCE-induced oxidative DNA damage is questionable.

Dose-response relationship for rat liver DNA damage caused by 1,2-dimethylhydrazine

An experimental approach was taken to the question of dose-response curves for chemical carcinogenesis, using DNA damage as a biomarker. Female rats were given 13 different doses of 1,2-dimethylhydrazine (from 1.4 to 135000 μg/kg) and the subsequent hepatic DNA damage was determined by the alkaline elution technique. DMH doses below 450 μg/kg did not significantly damage DNA; all DMH doses of 1000 μg/kg or higher damaged rat hepatic DNA ( P < 0.05). In this study the x values (dose) ranged over five orders of magnitude and the y values (DNA damage) ranged 30-fold. Ten different regression models (linear, quadratic, cubic, power, and six nonlinear transition models) were compared in their ability to fit the experimental data. With respect to log transformed dose, the six nonlinear transition equations fit the data considerably better than the four power type of equations. A sigmoid model fit to the log transformed dose of 1,2-dimethlyhydrazine had an r 2 of 0.9979, a degree of freedom adjusted r 2 of 0.9969, a F-statistic of 1,457, and a fit standard error of 0.50. With respect to untransformed dose, only three equations (sigmoid, cascade and gaussian cumulative) could creditably fit the DMH data. The experimental results are interpreted with respect to hormesis, use of log transformed dose, sigmoid dose-response models, thresholds of biological response and cancer risk assessment.

Dose-response relationship for rat liver DNA damage caused by 49 rodent carcinogens

An experimental approach was taken to the question of dose-response curves for chemical carcinogenesis. DNA damage in female rat liver was chosen as the experimental parameter because all chemicals found to damage hepatic DNA were rodent carcinogens. The lowest dose causing DNA damage was determined for the 12 active chemicals (1,2-dibromoethane, 1,2-dibromo-3-chloropropane, 1,2-dichloroethane, 1,4-dioxane, methylene chloride, auramine O, Michler's ketone, selenium sulfide, 1,3-dichloropropene, 1,2-dimethylhydrazine, N-nitrosopiperidine and butylated hydroxytoluene). The resulting dose-response curves for rat hepatic DNA damage were plotted versus log of the molar dose (all activity was in five orders of magnitude) and versus percent of chemicals' oral rat LD 50 (most of the activity was in only two orders of magnitude). Dose-response studies of the active chemicals were analyzed by regression methods. With the exception of butylated hydroxytoluene, the dose-response curves fit a linear model well ( r 2 = 0.886) and a quadratic model even better ( r 2 = 0.947). Based on experimental data from 11 DNA-damaging carcinogens (a dose range of 6 orders of magnitude), an equation and graph of the dose-response relationship of an ‘average DNA-damaging carcinogen’ is presented over the x-axis dose range of eight orders of magnitude.

Effect of ten thiocompounds on rat liver DNA damage induced by a small dose of N-nitrosodimethylamine.

The use in a chemoprevention study of high doses of the genotoxic agent might result in erroneous information because of possible nonlinearity of pharmacokinetic processes and toxicity-induced derangement of physiological defense mechanisms. According to these premises ten thiocompounds, potentially active as inhibitors of metabolic activation and/or scavengers, were examined for their capability of reducing the frequency of liver DNA lesions induced by a very small dose of N-nitrosodimethylamine (NDMA). This was accomplished by means of a viscometric technique previously found suitable to detect a minimal amount of DNA fragmentation. Rats were injected i.p. or i.v. with 1 mmol/kg of thiocompound, 0.2 mg/kg NDMA given by gavage 1 h afterwards, and killed for DNA damage assessment 14 h later. Statistically significant changes of viscometric parameters, which are considered indicative of a protective activity, were produced by disulfiram (DSF), and to a lower extent by diethyldithiocarbamate (DEDTC). Any modification of NDMA-induced DNA damage was absent in rats pretreated with glutathione reduced form (GSH) and dimethyl sulfoxide (DMSO). Allyl disulfide (ADS), L-cysteine (CYS), N-acetylcysteine (NAC), alpha-mercaptopropionylglycine (MPG), ethylxanthic acid (PEX), and 2-mercaptoethane sulfonic acid (MESNA) increased in various degree the frequency of DNA-strand breaks. In subsequent experiments the protective activity of DSF was found to be dose-related, dependent on the time of administration, and greater by oral route. Taken as a whole, these results suggest that several putative anticarcinogens might be ineffective against the DNA-damage produced by the low doses encountered in human exposure.

Oxidative DNA damage in rat liver and kidney induced by peroxisome proliferators (POP) or ferric nitrilotriacetate(Fe-NTA)

Oxidative DNA damage in rat liver and kidney induced by peroxisome proliferators (POP) or ferric nitrilotriacetate(Fe-NTA)

Biochemical studies of six nitrogen-containing heterocycles in rat tissues

Female rats were dosed orally with one-fifth the LD 50 of either 1-nitrosopiperidine (a carcinogen), cyclohexylamine, piperidine, 4-carboxy-1-nitrosopiperidine, 4-cyclohexyl-1-nitrosopiperidine or 2,6-dimethyl-1-nitrosopiperidine at 21 and 4 hr before they were killed. The five noncarcinogenic compounds had no effects on any experimental variables examined [hepatic DNA damage, ornithine decarboxylase (ODC) activity, serum alanine aminotransferase (SGPT) activity, cytochrome P-450 and glutathione content]. After administration of 40 mg/kg of 1-nitrosopiperidine, marked hepatic DNA damage and a 3- to 7-fold increase in the activity of hepatic ODC were observed. 1-Nitrosopiperidine (120 mg/kg, 3/5 LD 50) caused DNA damage in rat liver and esophagus but not in leukocytes. This higher dose of 1-nitrosopiperidine also increased hepatic ornithine decarboxylase activity by 9-fold. Thus, this hepatic biochemical assay system correctly identified the one carcinogen and the five noncarcinogens in this series of six nitrogen-containing heterocycles.