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)

Clofibrate is a peroxisome proliferator that can cause hepatic cancer in rodents. It has been suggested that oxidative damage is involved in this hepatocarcinogenesis, although the data are conflicting. We confirmed that clofibrate causes oxidative damage in nuclei from the livers of mice treated with this substance, measured both as protein carbonyls and levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in DNA. In addition, clofibrate also affects mitochondria, causing elevated levels of carbonyls and 8-OHdG, increased state 4 respiration and decreased adenosine triphosphatase (ATPase) activity. No evidence for clofibrate-induced lipid peroxidation in mitochondria was obtained. We propose that mitochondria may be a major target of injury and a source of oxidative stress in clofibrate-treated animals.
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PMID:Mitochondrial damage by the "pro-oxidant" peroxisomal proliferator clofibrate. 1056 42

The effects of the peroxisome proliferators di-isononyl phthalate (DINP) and di-2-ethylhexyl phthalate (DEHP) were evaluated in young adult male cynomolgus monkeys after 14 days of treatment, with emphasis on detecting hepatic and other effects seen in rats and mice after treatment with high doses of phthalates. Groups of 4 monkeys received DINP (500 mg/kg/day), DEHP (500 mg/kg/day), or vehicle (0.5% methyl cellulose, 10 ml/kg) by intragastric intubation for 14 consecutive days. Clofibrate (250 mg/kg/day), a hypolipidemic drug used for cholesterol reduction in human patients was used as a reference substance. None of the test substances had any effect on body weight or liver weights. Histopathological examination of tissues from these animals revealed no distinctive treatment-related effects in the liver, kidney, or testes. There were also no changes in any of the hepatic markers for peroxisomal proliferation, including peroxisomal beta-oxidation (PBOX) or replicative DNA synthesis. Additionally, in situ dye transfer studies using fresh liver slices revealed that DINP, DEHP, and clofibrate had no effect on gap junctional intercellular communication (GJIC). None of the test substances produced any toxicologically important changes in urinalysis, hematology, or clinical chemistry; however, clofibrate produced some emesis, small increases in serum triglyceride, decreased calcium, and decreased weights of testes/epididymides and thyroid/parathyroid. The toxicological significance of these small changes is questionable. The absence of observable hepatic effects in monkeys at doses that produce hepatic effects in rodents suggests that DINP, DEHP, and clofibrate would also not elicit in primates other effects such as liver cancer. These data, along with results from in vitro hepatocyte studies, indicate that rodents are not good animal models for predicting the hepatic effects of phthalates in primates, including humans.
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PMID:Effects of di-isononyl phthalate, di-2-ethylhexyl phthalate, and clofibrate in cynomolgus monkeys. 1086 67

Aging sensitizes the liver to the hepatocarcinogenic effect of PPARalpha agonists via unknown mechanisms. This study was designed to investigate whether aging enhances the susceptibility of the liver to the anti-apoptotic effect of these chemicals. Since apoptosis serves to purge the liver of transformed cells, exaggerated inhibition of this process in aged livers may facilitate the progress of these cells to cancer. We quantified the effect of the PPARalpha agonists, clofibrate and Wy-14643, on the mRNA levels of various elements of the apoptotic machinery in male Fisher-344 rats ranging in age from immaturity (4-week-old), young adulthood (10-week-old), middle age (50-week-old), to senescence (100-week-old). Clofibrate and Wy-14643 either significantly diminished or exerted no effect on hepatic mRNA levels of several pro-apoptotic factors in immature, middle age and senescent animals. Unexpectedly, however, these PPARalpha agonists caused a remarkable 2- to 45-fold augmentation in the levels of the mRNA of Bax, caspase-2, and Fas mRNA in the young adult 10-week-old rats. A 47-75% decrease in the percent of apoptotic hepatocytes was observed only in 50- and 100-week-old rats treated with Wy-14643. Data suggest that activation of PPARalpha alters the balance between pro- and anti-apoptotic genes most significantly in livers of 50- and 100-week-old rats. Since suppression of apoptosis in the senescent liver is expected to diminish its ability to purge itself of already transformed cells, which may then progress to malignancy, exposure of senescent animals to PPARalpha agonists may be crucial to the ultimate outcome of liver cancer later in their life-span.
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PMID:Age-dependent effects of nongenotoxic hepatocarcinogens on liver apoptosis in vivo. 1266 31