Inhibition by indomethacin and 5,8,11,14-eicosatetraynoic acid of the induction of rat hepatic ornithine decarboxylase by the tumor promoters phenobarbital and 12-<i>O</i>-tetradecanoylphorbol-13-acetate <i>in vivo</i>

Rooijen, Lucio A.A. Van; Uijtewaal, B.; Bisschop, A.

doi:10.1093/carcin/8.1.191

Cited by 9 publications

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“…The results in Figure 7 suggest that the cyclooxygenase and PLA 2 inhibitors, indomethacin and BPB, have little effect on enhancement of hepatocyte DNA synthesis by PB and similar results were obtained with other liver promoters tested. Thus, despite evidence that such inhibitors impair the effects of PB as a promoter (Denda et al, 1994) and as an ornithine decarboxylase inducer (Van Rooijen et al, 1987) in vivo, the study suggests that direct promoter action on hepatocytes to stimulate DNA synthesis is not blocked by these inhibitors.…”

Section: Discussionmentioning

confidence: 60%

“…Further evidence to associate prostaglandins with the action of PB in rat liver comes from studies on ornithine decarboxylase regulation. Van Rooijen et al (1987) showed that the induction of ornithine decarboxylase by PB in vivo was blocked by indomethacin and by the cyclooxygenase/lipooxygenase inhibitor 5,8,11,14‐ eicosatetraynoic acid (ETYA). Using a different promoting regimen, Gupta et al (1989) found elevated levels of PGE 2 in the livers of rats fed a choline‐deficient diet and indomethacin was shown to suppress the induction of γ‐glutamyl transpeptidase‐positive foci in livers of initiated rats.…”

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confidence: 99%

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Stimulation of DNA synthesis by tumor promoters in primary rat hepatocytes is not mediated by arachidonic acid metabolites

Lee

Edwards

2001

Journal Cellular Physiology

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Studies in vivo using inhibitors of eicosanoid synthesis suggested that prostaglandins may play a role in mediating tumor promotion in liver by agents such as phenobarbital (PB). However, it is not clear whether any stimulation of arachidonic acid metabolism/prostaglandin formation results directly from the action of tumor promoters on hepatocytes or indirectly from effects of promoters on Kupffer cells or other non-hepatocytes. Our laboratory has been utilizing relatively pure populations of rat hepatocytes under the defined conditions of primary cultures, to investigate growth-stimulatory actions of tumor promoters, an important element in the promotion stage of carcinogenesis. It has been shown that most if not all liver tumor promoters tested stimulate hepatocyte DNA synthesis when added in combination with factors such as EGF, insulin, and glucocorticoid. In the present study, we sought evidence for a role of prostaglandins (PGs) in the direct growth-stimulatory actions of tumor promoters on hepatocytes. PGE(2), PGF(2 alpha), and PGD(2) cause concentration-dependent stimulation of hepatocyte DNA synthesis, while arachidonic acid was without any effect. PGE(2) and PGF(2 alpha) required the presence of dexamethasone to exert significant effects. These PGs did not further augment the stimulatory effect of EGF. In contrast, PGD(2) stimulated DNA synthesis in the presence or absence of insulin, dexamethasone, or EGF. The effect of tumor promoters on arachidonic acid metabolism, as measured by [(3)H]arachidonic acid release and PGE(2) production, was determined. The phorbol ester TPA significantly increased [(3)H]arachidonic acid release as well as PGE(2) formation in hepatocytes in line with known effects in other cell types. However, liver tumor promoters phenobarbital (PB), alpha-hexachlorocycohexane (HCH), 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT), and pregnenolone-16 alpha-carbonitrile (PCN) were without effects. Finally, inhibitors of arachidonic acid metabolism were tested for effects on the ability of TPA or liver tumor promoters to stimulate DNA synthesis by direct action on cultured hepatocytes. In all cases, lack of selective inhibition was observed. Taken together, the results show that while prostaglandins may directly stimulate DNA synthesis in hepatocytes, they are unlikely to mediate the direct growth-stimulatory actions of liver tumor promoters.

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Section: Discussionmentioning

confidence: 60%

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confidence: 99%

Stimulation of DNA synthesis by tumor promoters in primary rat hepatocytes is not mediated by arachidonic acid metabolites

Lee

Edwards

2001

Journal Cellular Physiology

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“…The induction of glycogenolysis after administration of phorbol ester [1,2], endotoxin [3] or platelet-activating factor [4] to the perfused liver was found to be meditated by eicosanoids produced in the liver. Eicosanoids were also reported to be involved in the induction of the enzyme ornithine decarboxylase in the liver after administration of phorbol ester in vivo [5][6][7]. Since phorbol ester and endotoxin were not able to induce these metabolic effects in isolated parenchymal liver cells, a new concept for the regulation of liver metabolism was presented (1)(2)(3)(4)6,8).…”

Section: Introductionmentioning

confidence: 99%

Cellular communication inside the liver. Binding, conversion and metabolic effect of prostaglandin D2 on parenchymal liver cells

Kuiper

Zijlstra

Kamps

et al. 1989

Biochemical Journal

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The major eicosanoid produced within the rat liver, prostaglandin (PG) D2, wa studied for its ability to interact with the various liver cell types. It appeared that PGD2 bound specifically to parenchymal liver cells, whereas the binding of PGD2 to Kupffer and endothelial liver cells was quantitatively unimportant. Maximally 700 pg of PGD2/mg of parenchymal-cell protein could be bound by a high-affinity site (1 x 10(6) PGD2-binding sites/cell). The recognition site for PGD2 is probably a protein because trypsin treatment of the cells virtually abolished the high-affinity binding. High-affinity binding of PGD2 was a prerequisite for the induction of a metabolic effect in isolated parenchymal liver cells, i.e. the induction of glycogenolysis. High-affinity binding of PGD2 by parenchymal cells was coupled to the conversion of PGD2 into three metabolites, whereas no conversion of PGD2 by Kupffer and endothelial liver cells was noticed. The temperature-sensitivity of the conversion of PGD2 was consistent with a conversion of PGD2 on or in the vicinity of the cell membrane. One of the PGD2 metabolites could be identified as 9 alpha, 11 beta-PGF2. It can be calculated that the conversion rate of PGD2 by parenchymal liver cells exceeds the production rate of PGD2 by Kupffer plus endothelial liver cells, indicating that PGD2 is meant to exert its activity within the liver. The present finding that PGD2 formed by the non-parenchymal liver cells is recognized by a specific receptor on parenchymal liver cells and that binding, conversion and metabolic effect of PGD2 are interlinked by this receptor provides further support for the specific role of PGD2 in the intercellular communication in the liver.

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Association of protein kinase C activation with induction of ornithine decarboxylase in murine but not human keratinocyte cultures

Fischer¹,

Lee²,

Maldve³

et al. 1993

Molecular Carcinogenesis

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The goal of this study was to compare the response of mouse epidermal keratinocytes (MEKs) and human epidermal keratinocytes (HEKs) to 12-O-tetradecanoylphorbol-13-acetate (TPA) with respect to the activation and downregulation of protein kinase C (PKC), the expression of c-jun and c-fos, and the expression and induction of ornithine decarboxylase (ODC) activity. Keratinocytes from adult CD-1 mice and from discarded adult human skin were grown in primary culture in a high-calcium serum-free medium that supported proliferation and differentiation. Immunoblotting of freshly isolated and cultured MEKs and HEKs for isozymes of protein kinase C revealed that fresh HEKs contained PKC alpha, PKC beta, and PKC delta; no PKC gamma, PKC epsilon, or PKC zeta were detected. In fresh MEKs, PKC alpha, PKC beta, PKC delta, and PKC zeta were observed, but not PKC gamma or PKC epsilon. After 2 wk in culture, the isozyme profiles of MEKs and HEKs were similar except that PKC gamma was noticeably present in HEK cultures. Activation of partially purified total PKC by TPA was similar in freshly isolated and cultured MEKs and HEKs, indicating that the two species were similar in this regard and that 2 wk of culture did not alter this characteristic. When MEK and HEK cultures were treated with TPA for 3 h, less than 30% of the control level of PKC activity was detected, indicating that TPA-induced downregulation of PKC was similar in MEKs and HEKs. After treatment with TPA, MEK cultures produced a large induction of both c-jun and c-fos mRNA by 60 min, as determined by northern blot analysis, and a large induction of ODC mRNA and enzyme activity by 6 h. TPA treatment of cultured HEKs, however, did not induce ODC activity; in fact, less activity, compared with that of control cultures, was observed. Northern blot analysis also revealed no increase in c-jun, c-fos, and ODC mRNA in HEKs. However, c-jun and c-fos mRNA and both ODC mRNA and enzyme activity were induced in HEKs fed growth factors after several days of deprivation. This suggests that the lack of ODC induction by TPA in HEKs is probably due to species differences in downstream steps in PKC signal transduction.

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Inhibition by indomethacin and 5,8,11,14-eicosatetraynoic acid of the induction of rat hepatic ornithine decarboxylase by the tumor promoters phenobarbital and 12-O-tetradecanoylphorbol-13-acetate in vivo

Cited by 9 publications

References 0 publications

Stimulation of DNA synthesis by tumor promoters in primary rat hepatocytes is not mediated by arachidonic acid metabolites

Stimulation of DNA synthesis by tumor promoters in primary rat hepatocytes is not mediated by arachidonic acid metabolites

Cellular communication inside the liver. Binding, conversion and metabolic effect of prostaglandin D2 on parenchymal liver cells

Association of protein kinase C activation with induction of ornithine decarboxylase in murine but not human keratinocyte cultures

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