Polyamine metabolism in regenerating livers from normal and hypocalcemic rats

Pr, Walker; Sikorska, Marianna; Jf, Whitfield

doi:10.1002/jcp.1040940111

Cited by 14 publications

(5 citation statements)

References 17 publications

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“…However, severe toxicity seen after CD and BrCC13 low-dose combina-tion treatment results in extensive liver necrosis and compromised levels of these enzymes. Both spermidine and spermine are necessary for liver regeneration (18, [48][49][50] and this is consistent with decrease in levels of liver SAT and N1-acetylspermidine observed in these animals in 24 hr compared to their zero time point CD controls, which indicates an effort to preserve these compounds and prevent their interconversion to putrescine. SAMD is involved in the synthesis of spermidine and spermine from putrescine (17,36), and is reported to be increased in rat liver after exposure to CC4 (38,41), particularly after a low subtoxic dose (38).…”

Section: Discussionsupporting

confidence: 86%

Perturbations in polyamines and related enzymes following chlordecone‐potentiated bromotrichloromethane hepatotoxicity

Rao

Young

Mehendale

1990

J. Biochem. Toxicol.

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The mechanism by which chlordecone (CD) amplifies the hepatotoxicity of halomethanes such as CCl4, CHCl3, and BrCCl3 has been a subject of intense study. Recent work has shown that suppression of hepatocellular regeneration leads to accelerated progression of liver injury leading to complete hepatic failure due to an unusual interaction between individually nontoxic low-dose combination of CD and CCl4. Since polyamines are involved in cell division, their levels reflect the extent to which there is suppression of hepatocellular regeneration during CD and CCl4 interaction. The present studies were designed to investigate the polyamine levels and associated enzymes in livers of rats treated with BrCCl3 alone or CD and BrCCl3 low-dose combination in order to confirm whether the sequence of events of hepatotoxicity is similar to that seen in CCl4 toxicity or that seen during CD and CCl4 interaction. The extent of liver toxicity in rats fed 10 ppm chlordecone (CD) for 15 days prior to the injection of a single low dose of BrCCl3 (15 microL/kg body weight) or after exposure to a high dose of BrCCl3 (80 microL/kg body weight) without CD pretreatment, was similar 6 and 24 hr later as assessed by plasma transaminase levels. There was also an increase in transaminase levels, in rats exposed to a single low dose of BrCCl3 alone (15 microL/kg body weight) but this increase was far below the high-dose exposure alone or the combination treatment. Hepatic levels of ornithine decarboxylase, S-adenosylmethionine decarboxylase, N1-acetylputrescine, N1-acetylspermidine, putrescine, spermidine, and spermine at the end of 24 hr increased after exposure to a low dose of BrCCl3 alone as compared to exposure to a high dose alone or the low-dose combination of CD and BrCCl3. Liver spermidine N1-acetyltransferase was elevated at 2, 6, and 24 hr after exposure to a high dose of BrCCl3 alone as compared to treatment with a low-dose combination of CD and BrCCl3 suggesting decreased synthesis of this enzyme, in spite of a greater need as seen from liver transaminase levels. In general, it was observed that there is significant elevation in some polyamines and related enzymes during toxicity of a low dose of BrCCl3 which seemed to stabilize within 24 hr. This was not observed with the other two groups of rats exposed either to BrCCl3 high dose alone or the low-dose combination of CD and BrCCl3.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Discussionsupporting

confidence: 86%

Perturbations in polyamines and related enzymes following chlordecone‐potentiated bromotrichloromethane hepatotoxicity

Rao

Young

Mehendale

1990

J. Biochem. Toxicol.

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“…and best known genes to be turned on (possibly by the c-myc regulator) is the gene coding for ornithine decarboxylase which may be involved in the stimulation of protein synthesis [62][63][64].…”

mentioning

confidence: 99%

“…To start growing, the hepatocytes in the liver remnant must stop degrading protein and pump more amino acids and glucose into themselves [64,79]. To do this, the cells display more insulin receptors on their surfaces and increase the hormone's effectiveness by extending the time insulin-receptor complexes spend on the cell surface [79].…”

mentioning

confidence: 99%

Calcium, cyclic AMP and protein kinase C ? partners in mitogenesis

Whitfield¹,

Durkin²,

Franks³

et al. 1987

Cancer Metast Rev

Self Cite

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Evidence is steadily mounting that the proto-oncogenes, whose products organize and start the programs that drive normal eukaryotic cells through their chromosome replication/mitosis cycles, are transiently stimulated by sequential signals from a multi-purpose, receptor-operated mechanism (consisting of internal surges of Ca2+ and bursts of protein kinase C activity resulting from phosphatidylinositol 4,5-bisphosphate breakdown and the opening of membrane Ca2+ channels induced by receptor-associated tyrosine-protein kinase activity) and bursts of cyclic AMP-dependent kinase activity. The bypassing or subversion of the receptor-operated Ca2+/phospholipid breakdown/protein kinase C signalling mechanism is probably the basis of the freeing of cell proliferation from external controls that characterizes all neoplastic transformations.

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“…We believe our results may be relevant to physiological contexts where polyamines may not be permanently elevated. There are numerous situations in which polyamine levels are increased episodically, such as during the cell cycle [Fuller et al, 1977] and after stimulation of quiescent tissues to proliferate [Walker et al, 1978]. Based on the results described here, we predict that if cells or tissues are exposed to a mutagen at such times when polyamines are elevated transiently, mutant recovery would be enhanced.…”

Section: Discussionmentioning

confidence: 62%

Polyamines modulate carcinogen-induced mutagenesis in vivo

Wallon

O’Brien

2005

Environ. Mol. Mutagen.

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Elevated polyamine levels as a consequence of targeted overexpression of ornithine decarboxylase (ODC) to murine skin enhance susceptibility to tumorigenesis in this tissue. A possible mechanism for the enhanced susceptibility phenotype is an increased sensitivity of tissues with elevated polyamine levels to the mutagenic action of carcinogens. To test this hypothesis, a transgenic mouse model containing the Big Blue transgene and also expressing a K6/ODC transgene was developed. Incorporation of the K6/ODC transgene into the Big Blue model did not affect the spontaneous lacI mutant frequency in either skin or epidermis of the double-transgenic mice. After skin treatment with single doses of either 7,12-dimethylbenz[a]anthracene or N-methyl-N'-nitro-N-nitrosoguanidine, however, the mutant frequency was significantly increased in the skin of double-transgenic Big Blue;K6/ODC mice compared to Big Blue controls. The increases in mutant frequency were clearly due to ODC transgene activity, since treatment of mice with the ODC inhibitor, alpha-difluoromethylornithine, completely abolished the difference in mutant frequencies between double-transgenic and Big Blue mice. These results demonstrate that intracellular polyamine levels modulate mutation induction following carcinogen exposure.

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Polyamine metabolism in regenerating livers from normal and hypocalcemic rats

Cited by 14 publications

References 17 publications

Perturbations in polyamines and related enzymes following chlordecone‐potentiated bromotrichloromethane hepatotoxicity

Perturbations in polyamines and related enzymes following chlordecone‐potentiated bromotrichloromethane hepatotoxicity

Calcium, cyclic AMP and protein kinase C ? partners in mitogenesis

Polyamines modulate carcinogen-induced mutagenesis in vivo

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