Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisome proliferators are a diverse group of chemicals that include several therapeutically used drugs (e.g., hypolipidemic agents), plasticizers and organic solvents used in the chemical industry, herbicides, and naturally occurring hormones. As the name implies, peroxisome proliferators cause an increase in the number and size of peroxisomes in the liver, kidney, and heart tissue of susceptible species, such as rats and mice. Long-term administration of peroxisome proliferators can cause liver cancer in these animals, a response that has been the central issue of research on peroxisome proliferators for many years. Peroxisome proliferators are representative of the class of nongenotoxic carcinogens that cause cancer through mechanisms that do not involve direct DNA damage. The fact that humans are frequently exposed to these agents makes them of particular concern to government regulatory agencies responsible for assuring human safety. Whether frequent exposure to peroxisome proliferators represents a hazard to humans is unknown; however, increased cancer risk has not been shown to be associated with long-term therapeutic administration of the hypolipidemic drugs gemfibrozil, fenofibrate, and clofibrate. To make sound judgments regarding the safety of peroxisome proliferators, the validity of extrapolating results from rodent bioassays to humans must be based on the agents' mechanism of action and species differences in biologic activity and carcinogenicity. The peroxisome proliferator-activated receptor alpha (PPARalpha), a member of the nuclear receptor superfamily, has been found to mediate the activity of peroxisome proliferators in mice. Gene-knockout mice lacking PPARalpha are refractory to peroxisome proliferation and peroxisome proliferator-induced changes in gene expression. Furthermore, PPARalpha-null mice are resistant to hepatocarcinogenesis when fed a diet containing a potent nongenotoxic carcinogen WY-14,643. Recent studies have revealed that humans have considerably lower levels of PPARalpha in liver than rodents, and this difference may, in part, explain the species differences in the carcinogenic response to peroxisome proliferators.
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PMID:Mechanism of action of the nongenotoxic peroxisome proliferators: role of the peroxisome proliferator-activator receptor alpha. 982 24

Chronic exposure to peroxisome proliferators (PP), including certain industrial and pharmaceutical chemicals, causes liver cancer in rodents. Continuous exposure to PP is needed for tumor development since the frequency of hepatocellular neoplasms is decreased in animals returned to control diet. To determine cellular and molecular events responsible for enhanced growth in PP-induced liver tumors, we evaluated the relationships of WY-14,643 levels, apoptosis, mitosis and cyclophilin-40 (Cyp-40) expression in regressing tumors induced by WY-14,643, a potent PP. Male F344 rats were fed WY-14,643 (0.1%) in the diet for 43 weeks and then switched to control diet for 2, 3, 5 or 36 days. Mean serum and hepatic concentrations of WY-14,643 were decreased as early as 2 days following removal of WY-14,643 as compared with rats continuously fed WY-14,643. Adenomas from rats maintained on WY-14,643 markedly compressed surrounding parenchyma. Evidence of adenoma regression was observed by 3 days of WY-14,643 withdrawal and was characterized by loss of compression. Decreased compression corresponded to increases in the apoptotic index and decreases in the mitotic index in regressing adenomas at 2, 3, and 5 days following the switch to control diet. Cyclophilins are multifunctional receptor proteins involved in numerous signal transduction pathways, including those mediated by cyclosporin, a liver tumor promoter in rats. Cyp-40 expression was markedly increased in adenomas from continuously exposed rats, but expression returned to levels similar to surrounding parenchyma in adenomas after 5 days of WY-14,643 withdrawal. Taken together, these results indicate that WY-14, 643-induced adenomas regress rapidly following withdrawal of the PP in association with declining liver WY-14,643 levels, suggesting that peroxisome proliferator-activated receptor alpha may mediate PP-induced alterations in mitogenic and/or apoptotic regulation in growing tumors, in conjunction with alterations in Cyp-40 signal transduction.
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PMID:Apoptosis, mitosis and cyclophilin-40 expression in regressing peroxisome proliferator-induced adenomas. 1075 99

Trichloroethylene (TCE) induces liver cancer in mice but not in rats. Three metabolites of TCE may contribute--chloral hydrate (CH), dichloroacetate (DCA), and trichloroacetate (TCA). CH and TCA appear capable of only inducing liver tumors in mice, but DCA is active in rats as well. The concentrations of TCA in blood required to induce liver cancer approach the mM range. Concentrations of DCA in blood associated with carcinogenesis are in the sub-microM range. The carcinogenic activity of CH is largely dependent on its conversion to TCA and/or DCA. TCA is a peroxisome proliferator in the same dose range that induces liver cancer. Mice with targeted disruptions of the peroxisome proliferator-activated receptor alpha (PPAR-alpha) are insensitive to the liver cancer-inducing properties of other peroxisome proliferators. Human cells do not display the responses associated with PPAR-alpha that are observed in rodents. This may be attributed to lower levels of expressed PPAR-alpha in human liver. DCA treatment produces liver tumors with a different phenotype than TCA. Its tumorigenic effects are closely associated with differential effects on cell replication rates in tumors, normal hepatocytes, and suppression of apoptosis. Growth of DCA-induced tumors has been shown to arrest after cessation of treatment. The DCA and TCA adequately account for the hepatocarcinogenic responses to TCE. Low-level exposure to TCE is not likely to induce liver cancer in humans. Higher exposures to TCE could affect sensitive populations. Sensitivity could be based on different metabolic capacities for TCE or its metabolites or result from certain chronic diseases that have a genetic basis.
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PMID:Mode of action of liver tumor induction by trichloroethylene and its metabolites, trichloroacetate and dichloroacetate. 1080 55

beta-Oxidation occurs in both mitochondria and peroxisomes. Mitochondria catalyze the beta-oxidation of the bulk of short-, medium-, and long-chain fatty acids derived from diet, and this pathway constitutes the major process by which fatty acids are oxidized to generate energy. Peroxisomes are involved in the beta-oxidation chain shortening of long-chain and very-long-chain fatty acyl-coenzyme (CoAs), long-chain dicarboxylyl-CoAs, the CoA esters of eicosanoids, 2-methyl-branched fatty acyl-CoAs, and the CoA esters of the bile acid intermediates di- and trihydroxycoprostanoic acids, and in the process they generate H2O2. Long-chain and very-long-chain fatty acids (VLCFAs) are also metabolized by the cytochrome P450 CYP4A omega-oxidation system to dicarboxylic acids that serve as substrates for peroxisomal beta-oxidation. The peroxisomal beta-oxidation system consists of (a) a classical peroxisome proliferator-inducible pathway capable of catalyzing straight-chain acyl-CoAs by fatty acyl-CoA oxidase, L-bifunctional protein, and thiolase, and (b) a second noninducible pathway catalyzing the oxidation of 2-methyl-branched fatty acyl-CoAs by branched-chain acyl-CoA oxidase (pristanoyl-CoA oxidase/trihydroxycoprostanoyl-CoA oxidase), D-bifunctional protein, and sterol carrier protein (SCP)x. The genes encoding the classical beta-oxidation pathway in liver are transcriptionally regulated by peroxisome proliferator-activated receptor alpha (PPAR alpha). Evidence derived from mice deficient in PPAR alpha, peroxisomal fatty acyl-CoA oxidase, and some of the other enzymes of the two peroxisomal beta-oxidation pathways points to the critical importance of PPAR alpha and of the classical peroxisomal fatty acyl-CoA oxidase in energy metabolism, and in the development of hepatic steatosis, steatohepatitis, and liver cancer.
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PMID:Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha: an adaptive metabolic system. 1137 35

Exposure to agonists of peroxisome proliferator-activated receptor alpha (PPARalpha) causes liver cancer in rodents, with aged animals being more susceptible than their younger counterparts to this effect. Treatment with these chemicals produced a five- to sevenfold higher yield of grossly visible hepatic tumors in old rats compared to young animals. The enhanced susceptibility of the aged livers to the carcinogenic effect of PPAR agonists could not be explained by differences in levels of peroxisomal and/or cell proliferation between young and old animals, as neither of these responses was exaggerated with aging. Reported studies have shown that activating PPARalpha results in the suppression of hepatic apoptosis. This effect is expected to diminish the ability of the liver to purge itself of pre-existing neoplastic cells, allowing them to progress to tumors. New findings from our laboratories show that the aged liver is exceedingly sensitive to the antiapoptotic effect of PPAR agonists. In addition, aged livers showed remarkably higher levels of the antiapoptotic protein Bcl-2 than livers of young, adult, and middle-aged animals. Interestingly, the PPARalpha agonist Wy-14,643 significantly diminished elements of the proapoptotic machinery (e.g., Bax, caspases, and fas) in the aged liver, while remarkably increasing elements of this machinery in younger animals. Taken together, while activation of PPARs appears to inhibit apoptosis in livers of senescent animals, activating these receptors seems to stimulate the apoptotic machinery in young animals. This paradoxical effect may be responsible for the exaggerated sensitivity of the aged liver to the carcinogenic effect of agents that activate PPARs.
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PMID:Enhanced hepatocarcinogenicity due to agonists of peroxisome proliferator-activated receptors in senescent rats: role of peroxisome proliferation, cell proliferation, and apoptosis. 1280 35

Lipid-lowering fibrate drugs function as agonists for the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha). Sustained activation of PPARalpha leads to the development of liver tumors in rats and mice. However, humans appear to be resistant to the induction of peroxisome proliferation and the development of liver cancer by fibrate drugs. The molecular basis of this species difference is not known. To examine the mechanism determining species differences in peroxisome proliferator response between mice and humans, a PPARalpha-humanized mouse line was generated in which the human PPARalpha was expressed in liver under control of the tetracycline responsive regulatory system. The PPARalpha-humanized and wild-type mice responded to treatment with the potent PPARalpha ligand Wy-14643 as revealed by induction of genes encoding peroxisomal and mitochondrial fatty acid metabolizing enzymes and resultant decrease of serum triglycerides. However, surprisingly, only the wild-type mice and not the PPARalpha-humanized mice exhibited hepatocellular proliferation as revealed by elevation of cell cycle control genes, increased incorporation of 5-bromo-2'-deoxyuridine into hepatocyte nuclei, and hepatomegaly. These studies establish that following ligand activation, the PPARalpha-mediated pathways controlling lipid metabolism are independent from those controlling the cell proliferation pathways. These findings also suggest that structural differences between human and mouse PPARalpha are responsible for the differential susceptibility to the development of hepatocarcinomas observed after treatment with fibrates. The PPARalpha-humanized mice should serve as models for use in drug development and human risk assessment and to determine the mechanism of hepatocarcinogenesis of peroxisome proliferators.
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PMID:Diminished hepatocellular proliferation in mice humanized for the nuclear receptor peroxisome proliferator-activated receptor alpha. 1517 93

Peroxisome proliferator-activated receptor alpha (PPARalpha) is responsible for peroxisome proliferator-induced pleiotropic responses, including the development of hepatocellular carcinoma in rodents. However, it remains to be determined whether activation of PPARalpha only in hepatocytes is sufficient to induce hepatocellular carcinomas. To address this issue, transgenic mice were generated that target constitutively activated PPARalpha specifically to hepatocytes. The transgenic mice exhibited various responses that mimic wild-type mice treated with peroxisome proliferators, including significantly decreased serum fatty acids and marked induction of PPARalpha target genes encoding fatty acid oxidation enzymes, suggesting that the transgene functions in the same manner as peroxisome proliferators to regulate fatty acid metabolism. However, the transgenic mice did not develop hepatocellular carcinomas, even though they exhibited peroxisome proliferation and hepatocyte proliferation, indicating that these events are not sufficient to induce liver cancer. In contrast to the transgenic mice, peroxisome proliferators activate proliferation of hepatic non-parenchymal cells (NPCs). Thus, activation of hepatic NPCs and/or associated molecular events is an important step in peroxisome proliferators-induced hepatocarcinogenesis.
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PMID:Hepatocyte-restricted constitutive activation of PPAR alpha induces hepatoproliferation but not hepatocarcinogenesis. 1733 54

A number of perfluorinated alkyl acids including perfluorooctanoic acid (PFOA) elicit effects similar to peroxisome proliferator chemicals (PPC) in mouse and rat liver. There is strong evidence that PPC cause many of their effects linked to liver cancer through the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR alpha). To determine the role of PPAR alpha in mediating PFOA transcriptional events, we compared the transcript profiles of the livers of wild-type or PPAR alpha-null mice exposed to PFOA or the PPAR alpha agonist WY-14,643 (WY). After 7 days of exposure, 85% or 99.7% of the genes altered by PFOA or WY exposure, respectively were dependent on PPAR alpha. The PPAR alpha-independent genes regulated by PFOA included those involved in lipid homeostasis and xenobiotic metabolism. Many of the lipid homeostasis genes including acyl-CoA oxidase (Acox1) were also regulated by WY in a PPAR alpha-dependent manner. The increased expression of these genes in PPAR alpha-null mice may be partly due to increases in PPAR gamma expression upon PFOA exposure. Many of the identified xenobiotic metabolism genes are known to be under control of the nuclear receptor CAR (constitutive activated/androstane receptor) and the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2). There was excellent correlation between the transcript profile of PPAR alpha-independent PFOA genes and those of activators of CAR including phenobarbital and 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) but not those regulated by the Nrf2 activator, dithiol-3-thione. These results indicate that PFOA alters most genes in wild-type mouse liver through PPAR alpha, but that a subset of genes are regulated by CAR and possibly PPAR gamma in the PPAR alpha-null mouse.
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PMID:Toxicogenomic dissection of the perfluorooctanoic acid transcript profile in mouse liver: evidence for the involvement of nuclear receptors PPAR alpha and CAR. 1828 Dec 56

Fenofibrate, widely used for the treatment of dyslipidemia, activates the nuclear receptor, peroxisome proliferator-activated receptor alpha. However, liver toxicity, including liver cancer, occurs in rodents treated with fibrate drugs. Marked species differences occur in response to fibrate drugs, especially between rodents and humans, the latter of which are resistant to fibrate-induced cancer. Fenofibrate metabolism, which also shows species differences, has not been fully determined in humans and surrogate primates. In the present study, the metabolism of fenofibrate was investigated in cynomolgus monkeys by ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOFMS)-based metabolomics. Urine samples were collected before and after oral doses of fenofibrate. The samples were analyzed in both positive-ion and negative-ion modes by UPLC-QTOFMS, and after data deconvolution, the resulting data matrices were subjected to multivariate data analysis. Pattern recognition was performed on the retention time, mass/charge ratio, and other metabolite-related variables. Synthesized or purchased authentic compounds were used for metabolite identification and structure elucidation by liquid chromatographytandem mass spectrometry. Several metabolites were identified, including fenofibric acid, reduced fenofibric acid, fenofibric acid ester glucuronide, reduced fenofibric acid ester glucuronide, and compound X. Another two metabolites (compound B and compound AR), not previously reported in other species, were characterized in cynomolgus monkeys. More importantly, previously unknown metabolites, fenofibric acid taurine conjugate and reduced fenofibric acid taurine conjugate were identified, revealing a previously unrecognized conjugation pathway for fenofibrate.
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PMID:Fenofibrate metabolism in the cynomolgus monkey using ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry-based metabolomics. 1925 19

The peroxisome proliferator-activated receptor alpha (PPARalpha, or NR1C1) is a nuclear hormone receptor activated by a structurally diverse array of synthetic chemicals known as peroxisome proliferators. Endogenous activation of PPARalpha in liver has also been observed in certain gene knockout mouse models of lipid metabolism, implying the existence of enzymes that either generate (synthesize) or degrade endogenous PPARalpha agonists. For example, substrates involved in fatty acid oxidation can function as PPARalpha ligands. PPARalpha serves as a xenobiotic and lipid sensor to regulate energy combustion, hepatic steatosis, lipoprotein synthesis, inflammation and liver cancer. Mainly, PPARalpha modulates the activities of all three fatty acid oxidation systems, namely mitochondrial and peroxisomal beta-oxidation and microsomal omega-oxidation, and thus plays a key role in energy expenditure. Sustained activation of PPARalpha by either exogenous or endogenous agonists leads to the development of hepatocellular carcinoma resulting from sustained oxidative and possibly endoplasmic reticulum stress and liver cell proliferation. PPARalpha requires transcription coactivator PPAR-binding protein (PBP)/mediator subunit 1(MED1) for its transcriptional activity.
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PMID:PPARalpha: energy combustion, hypolipidemia, inflammation and cancer. 2041 53


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