| 1. |
- Fridén, B, et al.
(författare)
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The effect of estramustine derivatives on microtubule assembly in vitro depends on the charge of the substituent.
- 1991
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Ingår i: Biochemical pharmacology. - 0006-2952. ; 42:5, s. 997-1006
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Tidskriftsartikel (refereegranskat)abstract
- Estramustine, and derivatives of estramustine with a charged substituent at position 17 on the estrogen moiety, have been investigated for their effects on bovine brain microtubules in vitro. The negatively charged estramustine phosphate has been found previously to be a microtubule-associated protein (MAP)-dependent microtubule inhibitor [Wallin M, Deinum J and Fridén B, FEBS Lett 179: 289-293, 1985]. In the present study the binding of estramustine phosphate to MAP2 and tau was investigated. Both these MAPs were found to have two to three binding sites for estramustine phosphate which is compatible with the reported number of basic amino acid repeats of these MAPs, considered to be the ultimate tubulin binding domains. The Kd for the binding of estramustine phosphate to MAP2 was estimated to be 20 microM at 4 degrees, and for the binding of tau, 200 microM. The rate of dissociation was very low (T1/2 greater than 2 hr), which indicates that the binding of estramustine phosphate may stabilize the protein-drug complex by changing the protein conformation. Two new negatively charged estramustine derivatives, estramustine sulphate and estramustine glucuronide, were found to be similar MAP-dependent microtubule inhibitors. The concentration for 50% inhibition of assembly was 100 microM for the sulphate derivative, the same as found previously for estramustine phosphate, and 250 microM for the more bulky estramustine glucuronide. A positively charged derivative, estramustine sarcosinate, did not inhibit microtubule assembly or alter the composition of the coassembled MAPs. The morphology of the microtubules was, however, affected. The uncharged estramustine bound to both tubulin and MAPs, but no effects were seen on microtubule assembly, the composition of coassembled MAPs or the microtubule morphology. Our results suggest that only negatively charged estramustine derivatives have a MAP-dependent microtubule inhibitory effect. The two new negatively charged derivatives could therefore be valuable tools in the study of tubulin-MAP interactions. The results also confirm that these interactions between tubulin and MAPs are mainly electrostatic.
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| 2. |
- Lundgren, B, et al.
(författare)
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Effects of dietary treatment with 11 dicarboxylic acids, diethylcarboxylic esters and fatty acids on peroxisomal fatty acid beta-oxidation, epoxide hydrolases and lauric acid omega-hydroxylation in mouse liver.
- 1992
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Ingår i: Biochemical Pharmacology. - 0006-2952 .- 1356-1839. ; 43:4
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Tidskriftsartikel (refereegranskat)abstract
- C57B1/6 male mice were exposed through their diet to 11 dicarboxylic acids, carboxylic acids and diethyldicarboxylesters for 10 days. For the diacids and diethylesters this treatment resulted in a chain length-dependent induction of lauryl-CoA oxidase and cyanide-insensitive palmitoyl-CoA oxidation activities. A chain length of 12 carbon atoms or more seemed to be necessary for induction of these two activities. In addition, the same chain length dependence was observed for induction of lauric acid omega + omega-1 hydroxylase activity and increase in the protein content of the mitochondrial fraction. Treatment with two "natural" fatty acids, i.e. lauric and palmitic acid gave no effect at all on these various parameters. In no case was induction of cytosolic and mitochondrial epoxide hydrolase activities observed. Instead, a slight decrease in these activities was observed after administration of diacids with a chain length of 4-8 carbon atoms, whereas microsomal epoxide hydrolase activity was concurrently induced.
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| 3. |
- Permadi, H, et al.
(författare)
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Effects of perfluoro fatty acids on xenobiotic-metabolizing enzymes, enzymes which detoxify reactive forms of oxygen and lipid peroxidation in mouse liver.
- 1992
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Ingår i: Biochemical Pharmacology. - 0006-2952 .- 1356-1839. ; 44:6
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Tidskriftsartikel (refereegranskat)abstract
- Male mice were exposed via their diet to perfluoro fatty acids of various chain-lengths (2-10 carbon atoms) at different doses (0.02 and 0.1% weight) and for different periods of time (2-10 days). Thereafter, we monitored effects on liver and body weights and a number of hepatic parameters, including mitochondrial protein content, microsomal contents of cytochromes P450 and b5, NADPH-cytochrome P450 reductase activity [measured as NADPH-cytochrome c reductase (EC 1.6.2.3)], microsomal and cytosolic epoxide hydrolase (EC 3.3.2.3) activities, cytosolic DT-diaphorase (EC 1.6.99.2), glutathione transferase (EC 2.5.1.18), glutathione peroxidase (EC 1.11.1.9) and superoxide dismutase (EC 1.15.1.1) activities, and levels of thiobarbituric acid-reactive material (as an indicator of lipid peroxidation) in the mitochondrial subfraction. The most dramatic changes observed were a 5-9-fold increase in mitochondrial protein, a 3-6-fold increase in the microsomal content of cytochrome P450, a 3-10-fold increase in cytosolic DT-diaphorase activity, an approximately 2-fold increase in cytosolic epoxide hydrolase activity and as much as a 60% decrease in the level of thiobarbituric acid-reactive compounds in the mitochondrial fraction. Smaller increases in microsomal epoxide hydrolase activity and decreases in cytosolic glutathione peroxidase activity were also observed. Of the perfluoro fatty acids tested, perfluorooctanoic acid caused the largest changes in the parameters examined here. Dietary exposure of mice to a 0.02% dose of this substance for 10 days results in a maximal or near-maximal effect in most cases.
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