3.1 Cytochemical, microbiochemical and molecular genetic analysis of chemical carcinogenesis

Bannasch, Peter; Hacker, Hans Jörg; Klimek, Fritz; Mayer, Doris; Stumpf, H; Zerban, Heide

doi:10.1016/s0079-6336(11)80168-3

Cited by 14 publications

(4 citation statements)

References 48 publications

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“…Its activity is generally decreased in preneoplastically and neoplastically transformed hepatocytes which may result in extensive glycogen storage. 33 Even though Cx32ko mice show a defect in glycogen mobilization upon adrenergic stimulation, 12 they do not show increased glycogen contents in their liver. 34 Under the assumption that a decrease in glucose-6-phosphatase activity as mediated by PB would be advantageous for tumor cells in liver, one would expect a stronger effect of the barbiturate in Cx32wt mice, which are sensitive to promotion by PB.…”

Section: Discussionmentioning

confidence: 99%

Effect of the tumor promoter phenobarbital on the pattern of global gene expression in liver of connexin32‐wild‐type and connexin32‐deficient mice

Stahl¹,

Ittrich²,

Marx‐Stoelting³

et al. 2005

Intl Journal of Cancer

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The antiepileptic drug phenobarbital (PB) is used frequently as a model tumor promoter in rodent liver. It is believed to increase the probability of cancer by accelerating the clonal expansion of cells transformed during tumor initiation. The molecular mechanism underlying this process is only partly understood but seems to require the function of connexin32 (Cx32), one of the 2 gap junction proteins expressed in hepatocytes. PB mediates transcriptional activation of various genes in liver but which of these are relevant for tumor promotion is unknown. We have used oligonucleotide microarrays to identify genes differentially modulated in expression by PB in liver of Cx32-wild-type and Cx32-null mice. Mice of both strains were kept on PB containing (0.05%) or control diet for 2 weeks. Total liver RNA was isolated from 3 mice per experimental group and reverse transcribed; cDNAs were hybridized to oligonucleotide microarrays and a gene-by-gene linear model was used for statistical analysis of data. Five genes were identified as induced or repressed in untreated Cx32-null as compared to untreated Cx32-wild-type mice. PB affected the expression of 53 genes, of which 13 code for members of Phase-I/II of drug metabolism, and 12 genes were differentially affected in expression by PB in Cx32-null as compared to Cx32-wild-type mice. Among the differentially affected genes that could be verified by quantitative RT-PCR or Western analysis were the insulin like growth factor binding protein-1, retinol dehydrogenase-6 and the Y-chromosomally located gene Dby, among which may be a candidate of relevance for PB-mediated tumor promotion.

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Section: Discussionmentioning

confidence: 99%

Effect of the tumor promoter phenobarbital on the pattern of global gene expression in liver of connexin32‐wild‐type and connexin32‐deficient mice

Stahl¹,

Ittrich²,

Marx‐Stoelting³

et al. 2005

Intl Journal of Cancer

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“…A variety of aberrations in carbohydrate metabolism, including changes in the activity of HK, have been observed in transplantable hepatomas (Weber, 1977) and in successive stages of hepatocarcinogenesis (Bannasch et al, 1991;Klimek and Ban- nasch, 1993). In order to gain further information on glucose utilization in hepatocellular tumours, we focused our investigations on HK, especially isoenzyme II isolated from the Morris hepatoma (MH) 3924A.…”

Section: Introductionmentioning

confidence: 99%

Microheterogeneity of cytosolic and membrane-bound hexokinase II in Morris hepatoma 3924A

Rempel

Bannasch

Mayer

1994

Biochemical Journal

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Phosphorylation of glucose by hexokinase is the key step in glucose and energy metabolism of the cell. In the Morris hepatoma 3924A, hexokinase II is the predominant hexokinase isoenzyme and occurs in the cytosol as well as bound to membranes. Hexokinase II was isolated by DEAE-cellulose chromatography from both the cytosolic and the mitochondria-enriched fractions and further resolved by hydrophobic-interaction chromatography on phenyl-Sepharose into two components designated hexokinase IIa and IIb. In both the soluble and the mitochondria-enriched fractions, type IIb was the predominant form, but the IIb/IIa ratio was higher in the particulate (6-8) as compared with the cytosolic fraction (1.5-2.0). Binding of the isolated forms of the enzyme to rat liver mitochondria resulted in a 2-10-fold activation of both subtypes. Biochemical characterization showed that both subtypes are closely related to the isoenzyme commonly referred to as hexokinase II, and that the microheterogeneity was not a consequence of contamination with hexokinase I or III. Both subtypes had a molecular mass of 110 kDa, they were inhibited by Pi at concentrations higher than 5 mM, and activated by the detergent CHAPS. The two subtypes differed in electrophoretic mobility (IIa > IIb), in Km values for glucose (IIa, 0.109 mM; IIb, 0.216 mM), in Ki values for glucose 6-phosphate (IIa, 25 microM; IIb, 0.106 mM), and in Ki values for glucose 1,6-biphosphate (IIa, 12.2 microM; IIb, 5.5 microM). An artificial proteolytic cleavage as cause of the hexokinase II microheterogeneity can be excluded, since both subtypes show the same molecular mass and the ability to bind to mitochondria and phenyl-Sepharose. In addition, the relative proportions of the two subtypes did not vary markedly between several enzyme preparations. Northern-blot analysis with a hexokinase II-specific cDNA probe revealed two distinct mRNA transcripts of 5.2 and 6.3 kb in length, which offers the possibility that hexokinase II microheterogeneity is due to differential RNA transcription and/or processing.

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“…The G6PDH activity is upregulated in proliferating cells, including cancer cells [63,[81][82][83][84][85][86], particularly to provide NADPH as reducing power. Likewise, oxidative stress also induces G6PDH activity [66][67][68]71,87,88].…”

Section: Nadph Productionmentioning

confidence: 99%

Reduced nicotinamide adenine dinucleotide phosphate and the higher incidence of pollution‐induced liver cancer in female flounder

Köehler

Noorden

2003

Enviro Toxic and Chemistry

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In biological effect monitoring programs, induction of biotransformation and detoxification enzymes is used as a biomarker for pollution. Yet sex differences are usually neglected in the availability of reduction equivalents needed in these metabolic pathways and may affect biomarker responses. For example, female flounder have a threefold higher incidence of macroscopic liver nodules than males of the same age class in polluted environments of the North Sea that progress toward carcinomas, whereas tumors in males virtually never develop into cancer. Evidence is presented in this review that NADPH plays a significant role in this sex-related response to xenobiotics in liver of flounder. The NADPH is needed for biosynthesis, particularly of lipids and lipoproteins, and detoxification processes such as one-electron and two-electron biotransformation and conjugation and, therefore, its availability as substrate determines biomarker responses. Biotransformation of xenobiotics is more strongly induced and conjugation processes are less affected in male flounder liver during exposure. In female liver, NADPH is required for production of the yolk precursor protein vitellogenin for oocyte production. The latter process has a higher priority than the NADPH-requiring detoxification processes because reproductive success is more relevant in evolutionary perspectives than the survival of the individual female. The data reviewed here suggest that these sex-related differences in NADPH metabolism are a major cause of the higher incidence of liver cancer in female flounder in polluted environments.

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3.1 Cytochemical, microbiochemical and molecular genetic analysis of chemical carcinogenesis

Cited by 14 publications

References 48 publications

Effect of the tumor promoter phenobarbital on the pattern of global gene expression in liver of connexin32‐wild‐type and connexin32‐deficient mice

Effect of the tumor promoter phenobarbital on the pattern of global gene expression in liver of connexin32‐wild‐type and connexin32‐deficient mice

Microheterogeneity of cytosolic and membrane-bound hexokinase II in Morris hepatoma 3924A

Reduced nicotinamide adenine dinucleotide phosphate and the higher incidence of pollution‐induced liver cancer in female flounder

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