Mechanistically-based Human Hazard Assessment of Peroxisome Proliferator-induced Hepatocarcinogenesis

Ashby, John; Brady, A.M.; Elcombe, Cliff; Elliott, B.M.; Ishmael, Jane E.; Odum, J.; Tugwood, Jonathan; Kettle, S.; Purchase, I. F. H.

doi:10.1177/096032719401300201

Cited by 303 publications

(160 citation statements)

References 256 publications

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“…The noncarcinogens CINN, DCB, ETU, TMTU, and LIM also gave increases in labeling index; only DETU had no effect. Increases in labeling index produced by some of these compounds have been shown previously (27,30,31,34). All of the compounds tested gave increases in cytochrome P450, determined either as total (spectral) P450 or as specific isoforms (Western blots).…”

Section: Ratsupporting

confidence: 52%

“…Data were not subjected to statistical analysis. We set the criteria after viewing the data for the parameters determined and based the criteria on our experience of interpreting changes with these parameters, literature data where possible (27)(28)(29), and the actual data obtained. We accept that our criteria are arbitary and that other workers may have chosen to use different criteria (e.g., a 4-fold increase in cell proliferation representing a positive result rather than the 2-fold increase we have chosen).…”

Section: Resultsmentioning

confidence: 99%

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Prediction of rodent nongenotoxic carcinogenesis: evaluation of biochemical and tissue changes in rodents following exposure to nine nongenotoxic NTP carcinogens.

Elcombe

Odum

Foster

et al. 2002

Environ Health Perspect

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We studied nine presumed nongenotoxic rodent carcinogens, as defined by the U.S. National Toxicology Program (NTP), to determine their ability to induce acute or subacute biochemical and tissue changes that may act as useful predictors of nongenotoxic rodent carcinogenesis. The chemicals selected included six liver carcinogens (two of which are peroxisome proliferators), three thyroid gland carcinogens, and four kidney carcinogens. We administered the chemicals (diethylhexyl phthalate, cinnamyl anthranilate, chlorendic acid, 1,4-dichlorobenzene, monuron, ethylene thiourea, diethyl thiourea, trimethyl thiourea, and d-limonene to the same strains of mice and rats used in the original NTP bioassays (nine chemicals to rats and seven to mice). Selected tissues (liver, thyroid gland, and kidney) were collected from groups of animals at 7, 28, and 90 days for evaluation. Tissue changes selected for study were monitored for all of the test groups, irrespective of the specificity of the carcinogenic responses observed in those tissues. This allowed us to assess both the carcinogen specificity and the carcinogen sensitivity of the events being monitored. We studied relative weight, cell labeling indices, and pathologic changes such as hypertrophy in all tissues; a range of cytochrome P450 enzymes and palmitoyl coenzyme A oxidase in the liver; changes in the levels of plasma total triiodothyronine, total thyroxine, and thyroid-stimulating hormone (TSH) as markers of thyroid gland function; and hyaline droplet formation, tubular basophilia, and the formation of granular casts in the kidney. There were no single measurements that alerted specifically to the carcinogenicity of the agents to the rodent liver, thyroid gland, or kidney. However, in the majority of cases, the chemical induction of cancer in a tissue was preceded by a range of biochemical/morphologic changes, most of which were moderately specific for a carcinogenic outcome, and some of which were highly specific for it (e.g., increases in TSH in the thyroid gland and increases in relative liver weight in the mouse). The only measurements that failed to correlate usefully with carcinogenicity were the induction of liver enzymes (with the exception of the enzymes associated with peroxisome proliferation). Most of the useful markers were evident at the early times studied (7 days and 28 days), but no overall best time for the measurement of all markers was identified. The judicious choice of markers and evaluation times can aid the detection of potential nongenotoxic rodent carcinogens.

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Section: Ratsupporting

confidence: 52%

Section: Resultsmentioning

confidence: 99%

Prediction of rodent nongenotoxic carcinogenesis: evaluation of biochemical and tissue changes in rodents following exposure to nine nongenotoxic NTP carcinogens.

Elcombe

Odum

Foster

et al. 2002

Environ Health Perspect

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“…COX-2 is generally not expressed in normal tissue, whereas peroxisome proliferation is a phenotype of normal differentiated hepatocytes (16). Note that dexamethasone induces differentiation in many cell types and stimulates PPAR expression in primary hepatocytes (50), whereas it is a global inhibitor of COX-2 expression.…”

Section: Figmentioning

confidence: 99%

“…PPs cause an increase in the size and number of hepatic peroxisomes and enhanced expression of enzymes involved in fatty acid catabolism. Most PPs, or their direct metabolites, are structurally similar to fatty acids in being amphipathic carboxylic acids (16). Regulation of lipid metabolism and peroxisome proliferation by PPs occurs via activation of peroxisome-proliferator activated receptors (PPARs), members of the steroid receptor superfamily (17,18).…”

mentioning

confidence: 99%

Induction of Cyclooxygenase-2 Expression by Peroxisome Proliferators and Non-tetradecanoylphorbol 12,13-Myristate-type Tumor Promoters in Immortalized Mouse Liver Cells

Ledwith¹,

Pauley²,

Wagner³

et al. 1997

Journal of Biological Chemistry

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Increased expression of cyclooxygenase-2 (COX-2), the rate-limiting enzyme in prostaglandin synthesis, has been associated with growth regulation and carcinogenesis in several systems. COX-2 is known to be induced by cytokines and the skin tumor promoter 12-tetradecanoylphorbol-13-myristate (TPA). In the present study, we investigated the effects of several non-TPA-type tumor promoters on COX-2 expression in immortalized mouse liver cells. Specifically, we tested peroxisome proliferators (PPs), which are rodent liver tumor promoters that cause gross alterations in cellular lipid metabolism, the rodent liver tumor promoter phenobarbital, and the skin tumor promoters okadaic acid and thapsigargin. The PPs Wy-14643, mono-ethylhexyl phthalate, clofibrate, ciprofibrate ethyl ester, and eicosatetraynoic acid each caused large increases in COX-2 mRNA and protein, with maximal expression seen approximately 10 h after treatment of quiescent cells. COX-2 expression was also induced by thapsigargin, okadaic acid, and calcium ionophore A23187, but not by phenobarbital or the steroid PP dehydroepiandrosterone sulfate. Induction of COX-2 expression generally resulted in increased synthesis of prostaglandin E 2 (PGE 2 ). However, the PPs caused little or no increase in PGE 2 levels, and they inhibited serum-induced PGE 2 synthesis. Unlike nonsteroidal anti-inflammatory drugs, the PPs do not directly inhibit cyclooxygenase enzyme activity in vitro. Thus, PPs regulate prostaglandin metabolism via both positive (COX-2 induction) and inhibitory mechanisms. In summary, the strong induction of COX-2 expression by PPs, thapsigargin, and okadaic acid suggests a possible role for COX-2 in the growth regulatory activity of these non-TPA-type tumor promoters.

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“…In addition, clofibrate, that is also one of the peroxisome proliferators, is known to induce hepatocellular tumors in rats and mice [16]. Since it is known that clofibrate stimulates replicative DNA synthesis and cell division [2], it is assumed that the indirect DNA damage and some other promotional mechanism may be involved in its hepatocarcinogenesis. Therefore, peroxisome proliferators including DEHP have been recognized to induce hepatocellular tumors in rodents by a non-genotoxic pathway.…”

Section: Discussionmentioning

confidence: 99%

Susceptibility of Liver Proliferative Lesions in Heterozygous p53 Deficient CBA Mice to Various Carcinogens.

Uehara

Kashida

Watanabe

et al. 2002

The Journal of Veterinary Medical Science

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ABSTRACT. To investigate the liver tumorigenic sensitivity to various carcinogens in heterozygous p53 deficient [p53 (+/-)] CBA mice and their wild-type littermates [p53 (+/+) mice], 71 p53 (+/-) and 74 p53 (+/+) CBA mice (male, 6-12 weeks of age) were given diet containing 4,000 or 0 ppm flumequine (FL) for 26 weeks or a single intraperitoneal injection of 5 mg/kg body weights dimethylnitros amine (DMN) at start of the study in Exp. 1, diet containing 6,000 or 0 ppm di(2-ethylhexyl)-phthalate (DEHP) for 26 weeks in Exp. 2, or diet containing 12,000, 6,000 or 0 ppm phenolphthalein (PhP) for 26 weeks in Exp. 3. All surviving animals of these groups were killed after completion of treatment of the test substances for 26 weeks. In the FL groups, the incidences of hepatocellular altered f oci in p53 (+/-) mice, the multiplicities of those in p53 (+/-) and p53 (+/+) mice were significantly increased as compared to the corresponding control groups. The incidences and multiplicities of altered foci in the DMN groups were higher than those in the corresponding control groups in p53 (+/-) and p53 (+/+) mice, but no significant differences were indicated between the groups. There were no significant differences in the incidences, multiplicities and proliferating cell nuclear antigen labeling indices of altered foci in the FL or DMN groups between p53 (+/-) and p53 (+/+) mice. There were no significant differences in the incidences and multiplicities of altered foci between the DEHP or PhP and control groups. The present results suggest that p53 gene knocked out heterozygously does not enhance the chemical hepatocarcinogenesis in CBA mice. KEY WORDS: dimethylnitrosamine, di(2-ethylhexyl)-phthalate, flumequine, phenolphthalein, p53 (+/-) CBA mouse.

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Mechanistically-based Human Hazard Assessment of Peroxisome Proliferator-induced Hepatocarcinogenesis

Cited by 303 publications

References 256 publications

Prediction of rodent nongenotoxic carcinogenesis: evaluation of biochemical and tissue changes in rodents following exposure to nine nongenotoxic NTP carcinogens.

Prediction of rodent nongenotoxic carcinogenesis: evaluation of biochemical and tissue changes in rodents following exposure to nine nongenotoxic NTP carcinogens.

Induction of Cyclooxygenase-2 Expression by Peroxisome Proliferators and Non-tetradecanoylphorbol 12,13-Myristate-type Tumor Promoters in Immortalized Mouse Liver Cells

Susceptibility of Liver Proliferative Lesions in Heterozygous p53 Deficient CBA Mice to Various Carcinogens.

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