Requirement of Glutathione and Cysteine in Guanine-Specific Oxidation of DNA by Carcinogenic Potassium Bromate

Murata, Mariko; Bansho, Yuriko; Inoue, Sumiko; Ito, K.; Ohnishi, Shiho; Midorikawa, Katsumi; Kawanishi, Shosuke

doi:10.1021/tx000209q

Cited by 70 publications

(49 citation statements)

References 44 publications

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“…However, the finding that KBrO 3 exposure of female rats also increases BrdU-LI in PCT at doses of 250 and 500 ppm in spite of the absence of α2u-globulin indicates an involvement of some other mechanism. Considering that KBrO 3 might be reduced to form more reactive species at PCT, 34) the good correlation between the doses inducing 8-oxodG formation and elevation of BrdU-LI enables us to hypothesize that the cell proliferation observed in female rats might result from oxidative stress. 19,25) Since the histopathological findings and serum biochemical parameters indicate no obvious nephrotoxicity in female rats treated with KBrO 3 in the drinking water at any dose tested, oxidative stress might act via mitogenic stimulation.…”

Section: Discussionmentioning

confidence: 99%

Dose‐related changes of oxidative stress and cell proliferation in kidneys of male and female F344 rats exposed to potassium bromate

Umemura¹,

Kitamura²,

Kanki³

et al. 2004

Cancer Science

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It is still of importance to investigate renal carcinogenesis by potassium bromate (KBrO 3 ), a by-product of water disinfection by ozonation, for assessment of the risk to man. Five female F344 rats in each group were given KBrO 3 at a dose of 300 mg/kg by single i.g. intubation or at a dose of 80 mg/kg by single i.p. injection, and were killed 48 h after the administration for measurements of thiobarbituric acid-reactive substances (TBARS) and 8-oxodeoxyguanosine (8-oxodG) levels in the kidney. Both levels in the treated animals were significantly elevated as compared with the control values. In a second experiment, 5 male and female F344 rats in each group were administered KBrO 3 at concentrations of 0, 15, 30, 60, 125, 250 and 500 ppm in the drinking water for 4 weeks. KBrO 3 in the drinking water did not elevate TBARS in either sex at any of the doses examined, but 8-oxodG formation in both sexes at 250 ppm and above was significantly higher than in the controls. Additionally, the bromodeoxyuridine-labeling index for proximal convoluted tubules was significantly increased at 30 ppm and above in the males, and at 250 ppm and above in the females. α α α α2u-Globulin accumulation in the kidneys of male rats was increased with statistical significance at 125 ppm and above. These findings suggest that DNA oxidation induced by otassium bromate (KBrO 3 ) was at one time widely used as a maturing agent for flour and as a dough conditioner.1) It was, however, demonstrated to induce renal cell tumors in male and female F344 rats after oral administration for 2 years in the drinking water 2) and the use of KBrO 3 as a food additive is now limited or prohibited, so that exposure of humans via food is very low.3) Nevertheless, there is still concern regarding this chemical in the environment. In order to avoid the formation of trihalomethanes, major by-products in the process of drinking water chlorination 4) that are carcinogenic in rodents, 5) ozone disinfection has been proposed as an alternative method.6) However, it has been shown that ozonation of surface water can generate bromate as one of various by-products in treated drinking water, 7) implying a potential hazard. KBrO 3 has been classified as a genotoxic carcinogen based on positive mutagenicity in the Ames, 8) chromosome aberration 9) and micronucleus tests.10) It has the potential to induce 8-oxodeoxyguanosine (8-oxodG) formation both in vitro and in vivo, [11][12][13][14] and since ribo-and deoxyribonucleosides of 8-oxodG induce sister chromatid exchange in human lymphocytes 15) and 8-oxodG pairs with adenine as well as cytosine, generating GC-to-TA transversion upon replication by DNA polymerases, 16) it has been postulated that this oxidized base is responsible for the mutagenicity and carcinogenicity. 17,18) The formation of oxidized base also indicates that the intra-nuclear redox status is altered in an oxidative direction, and this may lead to the induction of aberrant transcriptional events. However, except for our previous paper, 19) we know of n...

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Section: Discussionmentioning

confidence: 99%

Dose‐related changes of oxidative stress and cell proliferation in kidneys of male and female F344 rats exposed to potassium bromate

Umemura¹,

Kitamura²,

Kanki³

et al. 2004

Cancer Science

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“…Cells (1 ϫ 10 6 cells) were resuspended in 1 ml cytoplasm extraction buffer, followed by treatment with trifluoroacetic acid according to the method as described previously (33). The GSH level was analyzed by HPLC with an Eicom electrochemical detector (ECD-300, Kyoto, Japan) with a gold disk electrode that can detect GSH (33,34).…”

Section: Materials-tas-103mentioning

confidence: 99%

Mechanism of Apoptosis Induced by a New Topoisomerase Inhibitor through the Generation of Hydrogen Peroxide

Mizutani¹,

Tada‐Oikawa²,

Hiraku³

et al. 2002

Journal of Biological Chemistry

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؉ levels preceded both increases in ⌬⌿m and DNA ladder formation. Inhibitors of NAD(P)H oxidase prevented TAS-103-induced apoptosis, suggesting that NAD(P)H oxidase is the primary enzyme mediating H 2 O 2 formation. Expression of the antiapoptotic protein, Bcl-2, in BJAB cells drastically inhibited TAS-103-induced apoptosis, confirming that H 2 O 2 generation occurs upstream of mitochondrial permeability transition. Therefore, these findings indicate that DNA cleavage by TAS-103 induces PARP hyperactivation and subsequent NAD ؉ depletion, followed by the activation of NAD(P)H oxidase. This enzyme mediates O 2 ؊ -derived H 2 O 2 generation, followed by the increase in ⌬⌿m and subsequent caspase-3 activation, leading to apoptosis.

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“…8 This compound has been shown to cause oxidative modification of DNA bases, lipids and proteins in kidneys. 9,10 Additionally, KBrO 3 is known to decrease the activity of an important antioxidative enzymeglutathione peroxidase, and to increase the formation of the following free radicals and reactive oxygen species: superoxide anion radical (O 2 ÀÁ ), nitric oxide (NO Á ), and peroxynitrite anion (ONOO À ).…”

Section: Introductionmentioning

confidence: 99%

Protective effects of melatonin and indole‐3‐propionic acid against lipid peroxidation, caused by potassium bromate in the rat kidney

Karbownik

Stasiak

Zygmunt

et al. 2006

Cell Biochemistry & Function

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Potassium bromate (KBrO(3)) is classified as a carcinogenic agent. KBrO(3) induces tumors and pro-oxidative effects in kidneys. Melatonin is a well known antioxidant and free radical scavenger. Indole-3-propionic acid (IPA), an indole substance, also reveals antioxidative properties. Recently, some antioxidative effects of propylthiouracil (PTU)-an antithyroid drug-have been found. The aim of the study was to compare protective effects of melatonin, IPA, and PTU against lipid peroxidation in the kidneys and blood serum and, additionally, in the livers and the lungs, collected from rats, pretreated with KBrO(3). Male Wistar rats were administered KBrO(3) (110 mg/kg b.w., i.p., on the 10th day of the experiment) and/or melatonin, or IPA (0.0645 mmol/kg b.w., i.p., twice daily, for 10 days), or PTU (0.025% solution in drinking water, for 10 days). The level of lipid peroxidation products-malondialdehyde + 4-hydroxyalkenals (MDA + 4-HDA)-was measured spectrophotometrically in thyroid homogenates. KBrO(3), when injected to rats, significantly increased lipid peroxidation in the kidney homogenates and blood serum, but not in the liver and the lung homogenates. Co-treatment with either melatonin or with IPA, but not with PTU, decreased KBrO(3)-induced oxidative damage to lipids in the rat kidneys and serum. In conclusion, melatonin and IPA, which prevent KBrO(3)-induced lipid peroxidation in rat kidneys, may be of great value as protective agents under conditions of exposure to KBrO(3).

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Requirement of Glutathione and Cysteine in Guanine-Specific Oxidation of DNA by Carcinogenic Potassium Bromate

Cited by 70 publications

References 44 publications

Dose‐related changes of oxidative stress and cell proliferation in kidneys of male and female F344 rats exposed to potassium bromate

Dose‐related changes of oxidative stress and cell proliferation in kidneys of male and female F344 rats exposed to potassium bromate

Mechanism of Apoptosis Induced by a New Topoisomerase Inhibitor through the Generation of Hydrogen Peroxide

Protective effects of melatonin and indole‐3‐propionic acid against lipid peroxidation, caused by potassium bromate in the rat kidney

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