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PubMed1992

Differences in the response of Sprague-Dawley and Lewis rats to bezafibrate: the hypolipidemic effect and the induction of peroxisomal enzymes.

The effects of bezafibrate administered at 10 and 50 mg/kg/day for 7 days to male Sprague-Dawley (SD) and Lewis rats were investigated in order to determine the interrelation between the changes in serum and hepatic lipid contents and activities of selected peroxisomal, microsomal and mitochondrial enzymes in the two rat strains. In both strains, bezafibrate effectively reduced serum and hepatic lipids, increased the liver weight, induced a proliferation of peroxisomes, and selectively elevated the activities of carnitine acetyltransferase and of the enzymes of the peroxisomal beta-oxidation system. Moreover, immunoblotting revealed that the drug specifically enhanced the concentration of only those peroxisomal enzymes involved in fatty acid beta-oxidation. The data obtained demonstrate that although the responses initiated by bezafibrate are qualitatively similar in both strains, they differ in their magnitude in a dose-dependent manner, with the Lewis strain exhibiting a more pronounced response than the SD rats. These results show that dose-dependent strain differences as well as the generally known species differences should be taken into account in pharmacological and toxicological evaluations of fibrates in rodents. Furthermore, generalization and extrapolation from rodent studies should be treated with great caution.

Animals↗
PubMed1984

In vitro activity of imipenem--a review.

A review is given of the microbiological properties of imipenem, a new carbapenem antibiotic with an exceptionally broad spectrum of antibacterial activity. An evaluation of results of numerous in vitro studies reveals that imipenem effectively inhibited growth of 53 of 55 bacterial species, the mean MIC90 being less than 8 mg/l. The MIC90 for cocci, with the exception of Staphylococcus epidermidis, is in the range of 0.01-3.1 mg/l. The MIC90 for all Enterobacteriaceae is equal to or less than 8 mg/l. Pseudomonas aeruginosa and other non-fermentative gram-negative bacteria are generally susceptible to imipenem, only Pseudomonas maltophilia and Pseudomonas cepacia showing intrinsic resistance. Imipenem is currently the most active drug available against anaerobic bacteria, the MIC usually being below 1 mg/l even for Bacteroides fragilis. Rare bacteria such as Nocardia asteroides, Listeria monocytogenes or fast growing Mycobacterium spp. which cause difficult-to-treat infections are also susceptible to imipenem. Increases in inoculum size have only a minimal effect on activity of the drug. In most species the MBC only slightly exceeded the MIC; however in the case of Streptococcus faecalis the MBC value was many times the MIC value. Synergism has been observed in combinations of imipenem with aminoglycosides, and antagonism in combinations with other beta-lactam antibiotics against Pseudomonas aeruginosa and Serratia marcescens. Imipenem is stable in the presence of the common chromosomal and plasmid-mediated enzymes. Induction of inactivating enzymes was observed in staphylococci, Pseudomonas aeruginosa and Serratia marcescens.

Anti-Bacterial Agents↗
PubMed1999

Species differences in induction of hepatic enzymes by BM 17.0744, an activator of peroxisome proliferator-activated receptor alpha (PPARalpha).

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 beta-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 < or =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 beta-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 demonstrated a real transcriptional activation. BM 17.0744 activates peroxisome proliferator-activated receptor alpha (PPARalpha), which could be shown by transactivation assays. The stimulation of PPARalpha by BM 17.0744 was stronger than that of the known ligands WY 14.643 and ETYA. Activation of PPARgamma can be excluded. Taken collectively, the data demonstrate an enhancement of the beta-oxidation system by BM 17.0744 paralleled by lipid-lowering in all species investigated. The activation of the nuclear factor PPARalpha 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 beta-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.

Animals↗
PubMed1992

Antigenic cross-reactivity among monoterpene cyclases from grand fir and induction of these enzymes upon stem wounding.

A major wound response in grand fir (Abies grandis) sapling stems is the rapid increase in monoterpene production at the site of injury. Monoterpene cyclases (synthases) catalyze the formation of monoterpenes from geranyl pyrophosphate, and total cyclase activity increases markedly on wounding. At least six distinct cyclases, producing different monoterpene products, have been isolated from wounded grand fir saplings and characterized. The predominant wound-inducible cyclase produces both alpha- and beta-pinene. This pinene cyclase was purified, and polyclonal antibodies were generated in rabbits against the sodium dodecyl sulfate-denatured protein. The antibody preparation was found to cross-react by Western blotting with other grand fir monoterpene cyclases that produce different olefinic products, but not with monoterpene cyclases from related conifer species (Pinus contorta and P. ponderosa) or from angiosperms (Mentha piperita and M. spicata). The increase in monoterpene cyclase activity after wounding was closely correlated with the appearance of new cyclase protein as determined by immunoblotting. These results indicate that the wound-dependent increase in monoterpene cyclase activity is a consequence of de novo synthesis of cyclase protein.

Antibodies↗
PubMed1988

On the mechanism of induction of the enzyme systems for peroxisomal beta-oxidation of fatty acids in rat liver by diets rich in partially hydrogenated fish oil.

In this paper, we describe the early biochemical changes in liver cells that occur in rats fed a semisynthetic diet containing 20% (w/w) partially hydrogenated fish oil. Within hours the level of ornithine decarboxylase (ODC) increased, peaked at about 24 h (11-fold increase) and returned to subnormal levels within 48 h. The diet evoked a similar rapid increase in the cellular level of mRNA for the bifunctional enzyme of peroxisomal beta-oxidation (enoyl-CoA hydratase: beta-hydroxyacyl-CoA dehydrogenase (HD)) (12-fold), followed by increases in the specific content of HD protein (3-fold) and the capacity for beta-oxidation in peroxisomes (5.3-fold). The cellular level of long-chain acyl-CoA increased 2.1-fold. By contrast, no significant changes were observed in the specific activities of ornithine decarboxylase, peroxisomal beta-oxidation activity and microsomal omega-hydroxylation as well as the level of long-chain acyl-CoA in livers of rats fed (1 week) diets containing 20% (w/w) soybean oil with added 3 or 6% (w/w) of either elaidic acid (18:1(11) (trans)), brassidic acid (22:1(13) (trans)) or erucic acid (22:1(13) (cis)). Expression of normal levels of mRNA for the bifunctional enzyme was also found. Morphometric analyses revealed no proliferation of peroxisomes in these fatty acid-supplemented diets, in contrast to that observed with the partially hydrogenated fish oil diet. These results are consistent with the proposal (Flatmark, T., Christiansen, E.N. and Kryvi, H. (1983) Biochim. Biohys. Acta 753, 460-466) that components in dietary oils, different from C22:1 cis and trans fatty acids, are responsible for the pleiotropic responses evoked in target cells. Thus, the pattern of response induced by partially hydrogenated fish oil mimics those induced by xenobiotic compounds collectively termed peroxisome proliferators.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1984

Induction of peroxisomal enzymes and palmitoyl-CoA hydrolase in rats treated with cholestyramine and nicotinic acid.

Male Wistar rats were given 200 mg/kg/day nicotinic acid or 1000 mg/kg/day cholestyramine by stomach tube for ten days. Peroxisomal palmitoyl-CoA oxidation (cyanide-insensitive) and the activities of palmitoyl-CoA hydrolase and urate oxidase were significantly increased in the total liver homogenate. Subcellular fractionation showed enhanced enzyme activities after drug treatment mainly in the peroxisome-containing fractions. The increase in urate oxidase activity and its subcellular distribution suggest that the tested drugs induce core-containing peroxisomes. The findings are similar to those previously reported with low doses of peroxisome-proliferating hypolipidemic drugs and with acetylsalicylic acid, a drug which is structurally similar to nicotinic acid. Since cholestyramine is not absorbed, its influence on hepatic enzymes probably occurs indirectly as a consequence of enhanced catabolism of cholesterol.

Animals↗
PubMed1992

Induction of peroxisomal enzymes and a 64-kDa peptide in cultured mouse macrophages treated with clofibrate.

The presence of catalase-containing particles was demonstrated in mouse macrophages of the cell line J774.3. These cells were incubated with clofibrate, a hypolipidemic drug known to cause peroxisome proliferation in rodent hepatocytes. The specific activities of catalase and fatty acid oxidase were significantly increased after 48 h incubation with 2 mM clofibrate. This response proved to be time and dose dependent. Other organelle marker enzymes showed little change in activity. Unexpectedly, clofibrate treatment also produced an increase in a 64-kDa peptide in these cells.

Animals↗