No measurable increase in thymidine glycol or 8-hydroxydeoxyguanosine in liver DNA of rats treated with nafenopin or choline-devoid low-methionine diet

Hegi, Monika E.; Ulrich, Dietmar; Sagelsdorff, Peter; Richter, Christoph; Lutz, Werner

doi:10.1016/0165-1110(90)90025-7

Cited by 43 publications

(7 citation statements)

References 18 publications

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“…These studies, therefore, suggest that a qualitative relationship between peroxisome proliferation, DNA oxidation and cancer in rodents may exist, although quantitative aspects of this mechanistic interrelationship have not been addressed. In contrast, elevations of 8-OHdG and HMdU were not observed in DNA from livers of rats following oral exposure to nafenopin (16) or WY-14,643 (17), respectively. Critical differences in compound selection, experimental design and methods may account for the apparent inconsistent elevation of oxidized nucleoside in DNA of PP-exposed rats in these studies.…”

Section: Introductionmentioning

confidence: 94%

Elevated 8-hydroxydeoxyguanosine in hepatic DNA of rats following exposure to peroxisome proliferators: relationship to carcinogenesis and nuclear localization

Cattley

Glover

1993

Carcinogenesis

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Increased oxidative DNA damage due to increased peroxisomal generation of H2O2 is a potential mechanism in the carcinogenicity of chemical peroxisome proliferators (PP) in rodent liver. In order to determine the relationship between carcinogenicity and peroxisome-dependent DNA damage, levels of DNA base oxidation were examined by comparing 8-hydroxydeoxyguanosine (8-OHdG) in DNA from unfractionated liver of male F344 rats following dietary exposure to PP [WY-14,643, 0.1% or 0.005%; di(2-ethylhexyl)phthalate (DEHP), 1.2%; clofibric acid, 0.5%] or phenobarbital (0.05%). Exposure-related increases in 8-OHdG were not observed at 3 or 11 weeks for any of the compounds fed. At 22 weeks, 8-OHdG was similarly elevated (2-3x) by WY-14,643 (0.1% and 0.005%) and clofibric acid (0.5%). These equivalent increases in 8-OHdG in DNA from unfractionated liver did not parallel the divergent carcinogenicity of these different dietary exposures in the present or previous studies. The potential oxidation of nuclear DNA was examined by comparing levels of 8-OHdG in DNA isolated from purified liver nuclei and unfractionated liver. Elevated levels of 8-OHdG were not detected in DNA isolated from nuclear fractions of livers from rats fed clofibric acid for 22 weeks, indicating the dependence of PP-induced oxidative DNA damage on extranuclear components of samples for DNA isolation. The absence of a quantitative relationship between PP-induced carcinogenicity and oxidative DNA base damage (as 8-OHdG), and the failure to localize this oxidative damage to nuclear DNA, suggest two possible conclusions: (1) quantitation of 8-OHdG, a specific and sensitive indicator of oxidative DNA damage, does not accurately reflect the potential peroxisomal H2O2-dependent DNA damage and carcinogenicity of PP exposure in rodents; (2) other hepatic responses may be more critical features of the mechanism of PP carcinogenicity.

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Section: Introductionmentioning

confidence: 94%

Elevated 8-hydroxydeoxyguanosine in hepatic DNA of rats following exposure to peroxisome proliferators: relationship to carcinogenesis and nuclear localization

Cattley

Glover

1993

Carcinogenesis

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“…Increased levels of 8-hydroxy-2 -deoxyguanosine, a biomarker of DNA damage caused by hydroxyl radicals, were also observed by some investigators in both the nuclei and mitochondria of rodent livers following treatment with ciprofibrate (21,32). In contrast, others have been unable to identify DNA damage or lipid peroxidation upon treatment with several PPs, including clofibrate (13,16), nor does increased acyl Co-A oxidase activity correlate with tumorigenic potency (27), though it has been shown to be a good marker for PP-induced cell proliferation (7).…”

Section: Introductionmentioning

confidence: 96%

Transcription Profiling Distinguishes Dose-Dependent Effects in the Livers of Rats Treated with Clofibrate

Kramer¹,

Blomme²,

Bunch³

et al. 2003

Toxicologic Pathology

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Peroxisome proliferators such as the fibrates act via the peroxisome proliferator activated receptor (PPAR)-α as hypolipidemic agents. Many peroxisome proliferators are also nongenotoxic hepatic carcinogens and hepatotoxicants in rodents. We performed transcription profiling using cDNA microarrays on livers of rats treated for 5 days with 3 doses of the peroxisome proliferator clofibrate. All 3 doses had hepatic effects as assessed by liver to body weight ratio, alanine aminotransferase (ALT) increases and histopathology examination. Analysis of the transcription profiling data identified changes in the expression of many genes within several mechanistic pathways that support existing hypotheses regarding peroxisome proliferator mediated carcinogenicity. Additionally, the transcription profiling, histopathology, and clinical chemistry results suggested a biphasic response to clofibrate. These findings provide insight into the pathogenesis of toxic and carcinogenic effects of clofibrate in rodents and demonstrate the ability of cDNA microarrays to provide information regarding mechanisms of toxicity identified during the drug development process.

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“…A number of indirect confirmations for DEHP-initiated increases in oxidants have been collected over past two decades [120,121,122,123,124,125]. It should be noted, however, that causative relevance of some of such evidence to the carcinogenic effect of PP in general, and DEHP in particular, has been questioned and contrasting views have been presented [126,127,128,129,130]. It has been shown that PPARα is required for generation of oxidants in mouse liver after prolonged [weeks, [131]], but not acute [hours, [132]] exposure to PPs.…”

Section: Production Of Reactive Oxygen Speciesmentioning

confidence: 99%

Modes of Action and Species-Specific Effects of Di-(2-ethylhexyl)Phthalate in the Liver

Rusyn

Peters

Cunningham

2006

Critical Reviews in Toxicology

245

141

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The industrial plasticizer di-(2-ethylhexyl)phthalate (DEHP) is used in manufacturing of a wide variety of polyvinyl chloride (PVC)-containing medical and consumer products. The biological action of DEHP is very similar to chemicals that are collectively known as peroxisome proliferators (PPs). PPs are a structurally diverse group of compounds characterized as nongenotoxic rodent carcinogens. This review focuses on the effect of DEHP in liver, a primary target organ for the pleiotropic effects of DEHP and other PPs. Specifically, liver parenchymal cells, identified herein as hepatocytes, are a major cell type that are responsive to exposure to PPs, including DEHP; however, other cell types in the liver may also play a role. The PP-induced increase in the number and size of peroxisomes in hepatocytes, so called 'peroxisome proliferation' that results in elevation of fatty acid metabolism, is a hallmark response to these compounds in the liver. A link between peroxisome proliferation and tumor formation has been a predominant, albeit questioned, theory to explain the cause of a hepatocarcinogenic effect of PPs. Other molecular events, such as induction of cell proliferation, decreased apoptosis, oxidative DNA damage, and selective clonal expansion of the initiated cells have been also been proposed to be critically involved in PP-induced carcinogenesis in liver. Considerable differences in the metabolism and molecular changes induced by DEHP in the liver, most predominantly the activation of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)α, have been identified between species. Both sexes of rats and mice develop adenomas and carcinomas after prolonged feeding with DEHP; however, limited DEHP-specific human data are available, even though exposure to DEHP and other phthalates is common in the general population. This likely constitutes the largest gap in our knowledge on the potential for DEHP to cause liver cancer in humans. Overall, it is believed that the sequence of key events that are relevant to DEHP-induced liver carcinogenesis in rodents involves the following events whereby the combination of the molecular signals and multiple pathways, rather than a single hallmark event (such as induction of PPARα and peroxisomal genes, or cell proliferation) contribute to the formation of tumors: (i) rapid metabolism of the parental compound to primary and secondary bioactive metabolites that are readily absorbed and distributed throughout the body; (ii) receptor-independent activation of hepatic macrophages and production of oxidants; (iii) activation of PPARα in hepatocytes and sustained increase in expression of peroxisomal and non-peroxisomal metabolismrelated genes; (iv) enlargement of many hepatocellular organelles (peroxisomes, mitochondria, etc.); (v) rapid, but transient increase in cell proliferation, and a decrease in apoptosis; (vi) sustained

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No measurable increase in thymidine glycol or 8-hydroxydeoxyguanosine in liver DNA of rats treated with nafenopin or choline-devoid low-methionine diet

Cited by 43 publications

References 18 publications

Elevated 8-hydroxydeoxyguanosine in hepatic DNA of rats following exposure to peroxisome proliferators: relationship to carcinogenesis and nuclear localization

Elevated 8-hydroxydeoxyguanosine in hepatic DNA of rats following exposure to peroxisome proliferators: relationship to carcinogenesis and nuclear localization

Transcription Profiling Distinguishes Dose-Dependent Effects in the Livers of Rats Treated with Clofibrate

Modes of Action and Species-Specific Effects of Di-(2-ethylhexyl)Phthalate in the Liver

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