ChemInform Abstract: HYPOLIPIDEMIC HEPATIC PEROXISOME PROLIFERATORS FORM A NOVEL CLASS OF CHEMICAL CARCINOGENS

Reddy, J. K.; Azarnoff, Daniel L.; Hignite, Charles E.

doi:10.1002/chin.198017325

Cited by 65 publications

(64 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…36,37 Most peroxisome proliferators exert their actions through peroxisome proliferator-activated receptors, which belong to the receptor superfamily of steroid hormone receptors. 38,39 However, several important differences between the hepatocellular alterations observed in this experiment and amphophilic preneoplastic foci deserve consideration:…”

Section: Discussionmentioning

confidence: 91%

Hepatocellular Alterations after Intraportal Transplantation of Ovarian Tissue in Ovariectomized Rats

Klotz

Hacker

Klingmüller

et al. 2000

The American Journal of Pathology

View full text Add to dashboard Cite

The mechanisms of hepatocarcinogenesis by certain synthetic estrogens seem to involve both nongenotoxic and indirect genotoxic effects. However, the natural estrogen estradiol did not exert any carcinogenic effects in established experimental protocols. To elucidate specific long-term effects of natural estrogens on hepatocytes, small pieces of ovarian tissue were transplanted via the portal vein into the livers of ovariectomized female rats. One week, 3 weeks, and 3 months after transplantation the transplants were found to proliferate and to secrete estradiol. Three weeks after transplantation the hepatocytes of the liver acini downstream of the stimulated transplants already showed a remarkable loss of glycogen, distinct cytoplasmic amphophilia, enlargement of their nuclei, a strong increase in the number and size of peroxisomes, an increase in proliferative activity and apoptotic elimination, and changes in the activity of certain key enzymes of energy metabolism. All hepatocellular alterations could be inhibited by the estrogen receptor antagonist toremifene and are, therefore, attributed to specific effects of estradiol produced by the transplants. The observed alterations resemble in some respects amphophilic preneoplastic liver foci, which particularly occur after long-term administration of nongenotoxic hepatocarcinogens, including the adrenal steroid hormone dehydroepiandrosterone. In a preliminary experiment three of six animals exhibited a hepatocellular carcinoma, and another animal developed a hepatocellular adenoma 18 months after intrahepatic ovarian tissue transplantation. A causal relationship between the use of oral contraceptive steroids and the development of hepatocellular adenomas in humans is now accepted, whereas a definite relationship between oral contraceptive use and malignant liver tumors has not yet been established. Nevertheless, some authors reported an increase in incidence of hepatocellular carcinomas in women using hormonal contraceptives for prolonged periods. [1][2][3] This was supported by long-term animal studies, which demonstrate an enhancement of hepatocarcinogenesis by various synthetic estrogens, eg, ethinyl estradiol and diethylstilbestrol. 4 -7 The mechanisms of estrogen carcinogenesis are quite complex: They include nongenotoxic, ie, proliferative effects via direct mitogenic action, as well as by enhancement of the effects of epidermal growth factor (EGF), hepatocyte growth factor (HGF), and transforming growth factor ␣ (TGF␣) on hepatocytes. 8 -10 Furthermore, genotoxic effects like the formation of DNA adducts and the generation of reactive intermediates (quinones) and free radicals, causing lipid peroxidation, have been identified. 11,12 Interestingly, the natural estrogen estradiol exerts stimulating effects on hepatocyte proliferation, whereas no carcinogenic effect of estradiol has been demonstrated so far. 13 Some of the carcinogenic effects of ethinyl estradiol can be inhibited by simultaneous application of estrogen receptor antagonists like tamoxifen, ...

show abstract

Section: Discussionmentioning

confidence: 91%

Hepatocellular Alterations after Intraportal Transplantation of Ovarian Tissue in Ovariectomized Rats

Klotz

Hacker

Klingmüller

et al. 2000

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…The ability of this compound to induce peroxisome proliferation has been implicated in its carcinogenicity, presumably through the production of oxygen radicals by these organelles (Reddy et al, 1980;Fahl et al, 1984). However, recent studies indicate that the ability of these compounds to induce sustained enhancement of liver cell proliferation, and not the degree of peroxisome proliferation, correlates with the degree of tumour response (Marsman et al, 1988).…”

Section: Discussionmentioning

confidence: 99%

“…Chronic administration of BR931 and other peroxisome proliferators results in the induction of hepatocellular carcinomas in rats and mice (Reddy et al, 1980;Butterworth et al, 1987;Rao & Reddy, 1987). The precise mechanism of their carcinogenicity is not well defined because classical genotoxicity tests have been negative (Reddy & Lalwani, 1983;Butterworth et al, 1987;Elliott & Elcombe, 1987) and tumour promotion studies have shown variable results (Popp et al, 1987).…”

mentioning

confidence: 99%

Changes in expression of cellular oncogenes and endogenous retrovirus-like sequences during hepatocarcinogenesis induced by a peroxisome proliferator

Shinozuka²,

Weinstein³

1991

Br J Cancer

View full text Add to dashboard Cite

Summary Previous studies have demonstrated that BR-931, a hepatic peroxisome proliferator, can induce liver tumours in mice and rats. Since alterations in gene expression may play a critical role in multistage hepatocarcinogenesis, the present studies examined the expression of the c-myc, c-H-ras, epidermal growth factor (EGF) receptor and ODC (ornithine decarboxylase) genes, as well as endogenous retrovirus-like sequences, in F344 rat liver during the first 8 weeks of feeding a 0.16% Br931 diet and in liver tumours induced by chronic feeding of this diet. Northern blot analysis of poly A+ liver RNA samples showed an increase in the level of RNAs homologous to rat leukaemia virus (RaLV) but no significant change in the level of 30S-retrovirus related RNAs in the liver RNA samples obtained from rats during the first 8 weeks of feeding the diet containing BR931. An increase in the levels of c-myc, c-H-ras and ODC transcripts was also seen in the liver RNA samples from the treated rats. Of particular interest was a decrease in the abundance of EGF receptor transcripts in the liver RNA samples from rats fed the BR931 diet. Increased levels of RaLV, c-myc, and ODC RNAs were also seen in the tumours induced by BR931, but this was not the case for 30S and c-H-ras. The liver tumour samples also showed a decrease in EGF receptor RNA. These changes in cellular levels of specific RNAs resemble, in several respect, those we previously described in rodent liver during regeneration and tumour promotion, and also those seen in rodent hepatomas induced by other agents. Therefore, they may reflect a common profile of gene expression relevant to liver proliferation and carcinogenesis.BR931, an ethanolamine derivative of Wy-14,633 [4-chloro-6-(2,3-xylidino)-2-pyrimidinythio]acetic acid, has been shown to possess both hypolipidemic and antiatherogenic properties, as well as induction of hepatomegaly and hepatic peroxisome proliferation (Sirtori et al., 1977;Reddy et al., 1987;Butterworth et al., 1987). Chronic administration of BR931 and other peroxisome proliferators results in the induction of hepatocellular carcinomas in rats and mice (Reddy et al., 1980;Butterworth et al., 1987;Rao & Reddy, 1987). The precise mechanism of their carcinogenicity is not well defined because classical genotoxicity tests have been negative (Reddy & Lalwani, 1983;Butterworth et al., 1987;Elliott & Elcombe, 1987) , 1989).There is accumulating evidence that altered expression of specific cellular proto-oncogenes is associated with carcinogenesis and tumour formation (Bishop, 1987;Weinberg, 1989). In previous studies from this laboratory, enhanced expression of endogenous retrovirus-related sequences has also been found in carcinogen-induced rat liver and colon tumours (Hsieh et al., 1987;Guillem et al., 1988), and during liver cell proliferation after partial hepatectomy (Hsiech et al., 1988). We have also observed increased expression of these endogenous retrovirus-like sequences in carcinogen-or UV-treated rat fibroblast cell cultures (Lambert e...

show abstract

“…WY-14643 stimulates peroxisome proliferation and is a nongenotoxic mitogen (67,68) Figure 6. Morphologic changes and serum a-fetoprotein (AFP) levels during cyclic feeding of a-acetylaminofluorene (AAF).…”

Section: Carcinogen-induced Oval Cell Proliferationmentioning

confidence: 99%

Cellular origin of cancer: dedifferentiation or stem cell maturation arrest?

Sell

1993

Environ Health Perspect

191

View full text Add to dashboard Cite

Given the fundamental principle that cancer must arise from a cell that has the potential to divide, two major nonexclusive hypotheses of the cellular origin of cancer are that malignancy arises a) from stem cells due to maturation arrest or b) from dedifferentiation of mature cells that retain the ability to proliferate. The role of stem cells in carcinogenesis is clearly demonstrated in teratocarcinomas. The malignant stem cells of teratocarcinomas are derived from normal multipotent stem cells and have the potential to differentiate into normal benign mature tissue. A widely studied model supporting dedifferentiation has been the putative origin of hepatocarcinomas from "premalignant" foci and nodules induced in the rat liver by chemicals. However, the dedifferentiation concept for hepatocarcinogenesis is challenged by more recent interpretations indicating that hepatocellular carcinoma arises from maturation arrest caused by abherrant differentiation of determined stem cells. Either hypothesis is supported by the cellular changes that occur in the rodent liver after different hepatocarcinogenic regimens. The formation of foci and nodules from altered hepatocytes supports dedifferentiation; the proliferation of small oval cells with the potential to differentiate into either biliary ducts or hepatocytes supports arrested maturation of determined stem cells. It is now postulated that foci and nodular change reflect adaptive changes to the toxic effects of carcinogens and not "preneoplastic" stages to cancer. The stem cell model predicts that genotoxic chemicals induce mutations in the determined stem cell which may be expressed in its progeny. Proliferation of initiated cells is induced by promoting events which also allow additional mutations to occur.

show abstract

ChemInform Abstract: HYPOLIPIDEMIC HEPATIC PEROXISOME PROLIFERATORS FORM A NOVEL CLASS OF CHEMICAL CARCINOGENS

Cited by 65 publications

References 1 publication

Hepatocellular Alterations after Intraportal Transplantation of Ovarian Tissue in Ovariectomized Rats

Hepatocellular Alterations after Intraportal Transplantation of Ovarian Tissue in Ovariectomized Rats

Changes in expression of cellular oncogenes and endogenous retrovirus-like sequences during hepatocarcinogenesis induced by a peroxisome proliferator

Cellular origin of cancer: dedifferentiation or stem cell maturation arrest?

Contact Info

Product

Resources

About