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  • 1
    Electronic Resource
    Electronic Resource
    Species differences in induction of hepatic enzymes by BM 17.0744, an activator of peroxisome proliferator-activated receptor alpha (PPARα) (1999)
    Springer
    Archives of toxicology 73 (1999), S. 440-450 
    Details
    ISSN: 1432-0738
    Keywords: Key words BM 17.0744 ; β-Oxidation pathway ; Peroxisomes ; Peroxisome proliferators ; Species differences
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract BM 17.0744, a new anti-diabetic and lipid-lowering agent, leads also to strong hepatomegaly and carnitine acetyl transferase (CAT) increase in the liver of rats, a phenomenon known from fibrates. For information on the relevance of changes in liver of rats to other species, we investigated the effects of BM 17.0744 on lipids and selected marker enzymes related to β-oxidation in rats, dogs and guinea-pigs, so-called high and low responders to peroxisome proliferators. To examine selectivity other enzymes were also determined, e.g. esterase, urate oxidase (UOX) and cytochrome c oxidase (CYT.C.OX.). Lowering of triglycerides and cholesterol in blood serum and/or liver was observed in pharmacological dose range in the three species tested. In dogs and guinea-pigs, liver and kidney weights were unaffected even in dogs in medium and high dose groups with high systemic exposure and severe toxicity. In male Sprague-Dawley rats treatment with 1.5, 3, 6 and 12.5 mg/kg per day BM 17.0744 selectively elevated the activities of CAT and acyl-CoA oxidase (AOX) by ≤200 and 20-fold, respectively. Administration of BM 17.0744 to Beagle dogs (1.5, 4, 12 mg/kg per day) and guinea-pigs (3 and 12 mg/kg per day) enhanced the activities of CAT and AOX dose-dependently by a factor of two to three only. Immunoblotting revealed a drug-specific enhancement of the amount of β-oxidation enzymes in rats, which is in accord with the rapid and coordinated transcriptional activation shown in Northern dot blot analysis. Nuclear run-on assays demostrated a real transcriptional activation. BM 17.0744 activates peroxisome proliferator-activated receptor α (PPARα), which could be shown by transactivation assays. The stimulation of PPARα by BM 17.0744 was stronger than that of the known ligands WY 14.643 and ETYA. Activation of PPARγ can be excluded. Taken collectively, the data demonstrate an enhancement of the β-oxidation system by BM 17.0744 paralleled by lipid-lowering in all species investigated. The activation of the nuclear factor PPARα may explain the changes in liver and the metabolic effects on the molecular level. The lack of an increase in liver and kidney weights and the relatively moderate enhancement of activities of β-oxidation-related enzymes in dogs and guinea-pigs indicate that the excessive response observed in rats is not applicable to other, predominantly non-rodent, species. On the basis of these data and the experience with fibrates a specific risk for humans is not expected.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002040050633
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  • 2
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    Natural variability or anthropogenically-induced variation? Insights from 15 years of multidisciplinary observations at the arctic open-ocean LTER site HAUSGARTEN (2016)
    ELSEVIER SCIENCE BV
    In:  EPIC3Ecological Indicators, ELSEVIER SCIENCE BV, 65, pp. 89-102, ISSN: 1470-160X
    Details
    Publication Date: 2016-03-17
    Description: Time-series studies of arctic marine ecosystems are rare. This is not surprising since polar regions are largely only accessible by means of expensive modern infrastructure and instrumentation. In 1999, the Alfred-Wegener-Institut Helmholtz-Zentrum für Polar- und Meeresforschung (AWI) established the LTER (Long-Term Ecological Research) observatory HAUSGARTEN crossing the Fram Strait at about 79°N. Multidisciplinary investigations covering all parts of the open-ocean ecosystem are carried out at a total of 21 permanent sampling sites in water depths ranging between 250 and 5,500 m. From the outset, repeated sampling in the water column and at the deep seafloor during regular expeditions in summer months was complemented by continuous year-round sampling and sensing using autonomous instruments in anchored devices (i.e., moorings and free-falling systems). The central HAUSGARTEN station at 2,500 m water depth in the eastern Fram Strait serves as an experimental area for unique biological in situ experiments at the seafloor, simulating various scenarios in changing environmental settings. Long-term ecological research at the HAUSGARTEN observatory revealed a number of interesting temporal trends in numerous biological variables from the pelagic system to the deep seafloor. Contrary to common intuition, the entire ecosystem responded exceptionally fast to environmental changes in the upper water column. Major variations were associated with a warm water anomaly evident in surface waters in eastern parts of the Fram Strait between 2005 and 2008. However, even after 15 years of intense time-series work at HAUSGARTEN, we cannot yet predict with complete certainty whether these trends indicate lasting alterations due to anthropologically-induced global environmental changes of the system, or whether they reflect natural variability on multiyear time-scales, for example, in relation to decadal oscillatory atmospheric processes.
    Repository Name: EPIC Alfred Wegener Institut
    Type: Article , isiRev
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