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71.
72.
To gain insight into the spatial nature of the androstenedione (AD) binding (active) site of aromatase in relation to the catalytic function of the enzyme, we synthesized 2,2-dimethylAD (4), 2beta- and 2alpha-methylADs (5 and 6), 19-oxygenated derivatives of compounds 4 and 6, and 2-methyleneAD (17), and we then tested their inhibitory activity as well as their aromatase reaction (aromatization for 2-methyl and 2-methylene analogs or 19-oxygenation for 2,2-dimethyl steroids) with human placental aromatase. 2-Methyl and 2-methylene steroids 5, 6, and 17 were good competitive inhibitors of aromatase (K(i)=22-68nM), but less effective compared to the 2,2-dimethyl analog 4 (K(i)=8.8nM), indicating that a combination of 2beta- and 2alpha-methyl moieties is essential for the formation of a thermodynamically stable inhibitor-aromatase complex. A series of 2alpha-methyl steroids were good substrates for aromatase, whereas 2beta-methyl steroid 5 was an extremely poor substrate, and a series of 2,2-dimethyl steroids did not serve as substrate, suggesting that a 2beta-methyl moiety of the 2,2-dimethyl and 2beta-methyl steroids would prevent the aromatase reaction probably due to steric hindrance in each case. The 2-methylene compound 17 was also aromatized to produce 2-methylestrogen with a low conversion rate where the 1,4-diene structure may have been created before the C(10)-C(19) bond cleavage. Kinetic analysis of the aromatization of androgens revealed that a good substrate was not essentially a good inhibitor for aromatase. 相似文献
73.
Relationship between the action of reactive oxygen and nitrogen species on bilayer membranes and antioxidants 总被引:3,自引:0,他引:3
de Lima VR Morfim MP Teixeira A Creczynski-Pasa TB 《Chemistry and physics of lipids》2004,132(2):197-208
Membrane lipid peroxidation (LPO) induced by hydroxyl (*OH) and ascorbyl (*Asc) radicals and by peroxynitrite (ONOO-) was investigated in asolectin (ASO), egg phosphatidylcholine (PC) and PC/phosphatidic acid mixtures (PC:PA) liposomes and rat liver microsomes (MC). Enthalpy variation (DeltaH) of PC:PA at different molar ratios were obtained by differential scanning calorimetry. It was also evaluated the LPO inhibition by quercetin, melatonin and Vitamin B6. The oxidant effect power follows the order *OH approximately *Asc > ONOO- on PC and MC; whilst on ASO liposomes, it follows *Asc > *OH approximately ONOO-. Increasing amounts of PA in PC liposomes resulted in lower levels of LPO. The DeltaH values indicate a more ordered membrane arrangement as a function of PA amount. The results were discussed in order to provide a complete view involving the influence of membranes, oxidants and antioxidants intrinsic behavior on the LPO dynamics. 相似文献
74.
Flobufen (F) is an original nonsteroidal antiinflammatory drug that exists in two enantiomeric forms. Its biotransformation was investigated in male guinea pigs because of the similarities shown in a preliminary F metabolic study between guinea pig and man. Stereospecificity of the respective enzymes was studied in vitro, using microsomes and cytosol, and in vivo, in urine and feces. Rac-F, R-F, and S-F served as substrates. The amount of 4-dihydroflobufen stereoisomers (DHF) and other metabolites (M-17203 and UM-2) was determined by chiral HPLC using an R,R-ULMO column. It was observed that F reductases were distributed differently in microsomes and cytosol. The microsomal fraction showed higher activity and different stereospecificity in rac-F, R-F, and S-F reduction compared to cytosol. (2R;4S)-DHF was the principle metabolite in microsomes and (2S;4S)-DHF was the principle metabolite in cytosol. In vivo experiments revealed the excretion of a main metabolite UM-2 in addition to other metabolites M-17203 and DHF stereoisomers. UM-2 was predominantly excreted after S-F administration. Stereoselectivity of DHF stereoisomers excretion was different in urine and in feces. The absence of UM-2 and M-17203 in microsomes and cytosol and their presence in urine and feces showed that both could arise in some other extrahepatic tissue or cell compartment or that their formation depends on liver cell integrity. 相似文献
75.
Wheelock CE Wheelock AM Zhang R Stok JE Morisseau C Le Valley SE Green CE Hammock BD 《Analytical biochemistry》2003,315(2):208-222
Carboxylesterases hydrolyze many pharmaceuticals and agrochemicals and have broad substrate selectivity, requiring a suite of substrates to measure hydrolytic profiles. To develop new esterase substrates, a series of alpha-cyanoesters that yield fluorescent products upon hydrolysis was evaluated for use in carboxylesterase assays. The use of these substrates as surrogates for Type II pyrethroid hydrolysis was tested. The results suggest that these novel analogs are appropriate for the development of high-throughput assays for pyrethroid hydrolase activity. A set of human liver microsomes was then used to determine the ability of these substrates to report esterase activity across a small population. Results were compared against standard esterase substrates. A number of the esterase substrates showed correlations, demonstrating the broad substrate selectivity of these enzymes. However, for several of the substrates, no correlations in hydrolysis rates were observed, suggesting that multiple carboxylesterase isozymes are responsible for the array of substrate hydrolytic activity. These new substrates were then compared against alpha-naphthyl acetate and 4-methylumbelliferyl acetate for their ability to detect hydrolytic activity in both one- and two-dimensional native electrophoresis gels. Cyano-2-naphthylmethyl butanoate was found to visualize more activity than either commercial substrate. These applications demonstrate the utility of these new substrates as both general and pyrethroid-selective reporters of esterase activity. 相似文献
76.
77.
Angel Catalá 《Molecular and cellular biochemistry》1993,120(2):89-94
This paper reviews characteristics of microsomal membrane structure; long chain fatty acids, acyl CoA derivatives, retinoids and the microsomal formation of acyl CoA derivatives and retinyl esters. It is analyzed how the movement of these molecules at the intracellular level is affected by their respective binding proteins (Fatty acid binding protein, acyl CoA binding protein and cellular retinol binding protein). Studies with model systems using these hydrophobic ligands and the lipid-binding or transfer proteins are also described. This topic is of interest especially because in the esterification of retinol the three substrates and the three binding proteins may interact. (Mol Cell Biochem20: 89–94, 1993)Abbreviations FABP(s)
Fatty Acid Binding Protein(s)
- CRBP
Cellular Retinol Binding Protein
- ACBP
Acyl-CoA-Binding Protein 相似文献
78.
The effect of different doses of L-triiodothyronine (T3) on the activity of 6 and 5 desaturases and lipid fatty acid composition was studied in liver microsomes of male rats. The activity of 6 and 5 desaturases was decreased 24 and 28%, respectively, in animals administered a daily intraperitoneal dose of 1000g T3/100g body wt. for 5 days, whereas with 500g T3/100g body wt. only 6 desaturase activity was decreased. On the other hand, no enzyme activity changed at a shorter period of hormone treatment. Changes in microsomal fatty acid composition did not seem to be a direct consequence of desaturation activity, since after 1 and 5 days of T3 treatment, the concentrations of 18:2 (n-6) and 20:3 (n-6) decreased and only after 1 day that of 20:4 (n-6) increased in spite of unchanged or decreased 6 and 5 desaturase activities. Other factors than desaturation activity must be involved in fatty acid composition of thyroid hormonetreated rats, such as diet, membrane lipid synthesis and degradation, fatty acid turn-over and oxidation. (Mol Cell Biochem121: 149–153, 1993) 相似文献
79.
Oxidation of NADH by decavanadate, a polymeric form vanadate with a cage-like structure, in presence of rat liver microsomes followed a biphasic pattern. An initial slow phase involved a small rate of oxygen uptake and reduction of 3 of the 10 vanadium atoms. This was followed by a second rapid phase in which the rates of NADH oxidation and oxygen uptake increased several-fold with a stoichiometry of NADH: O2 of 11. The burst of NADH oxidation and oxygen uptake which occurs in phosphate, but not in Tris buffer, was prevented by SOD, catalase, histidine, EDTA, MnCl2 and CuSO4, but not by the hydroxyl radical quenchers, ethanol, methanol, formate and mannitol. The burst reaction is of a novel type that requires the polymeric structure of decavanadate for reduction of vanadium which, in presence of traces of H2O2, provides a reactive intermediate that promotes transfer of electrons from NADH to oxygen. 相似文献
80.
(1-14C) Eicosatetraenoic (Arachidonic) acid was incubated wiht microsomes from rabbit renal cortex and NADPH (1 mM) for 15 min at 37°C. The products were extracted and purified by high pressure liquid chromatography. Some of the most polar metabolites were identified by gas chromatography mass spectrometry. They were 11, 12, 19- and 11, 12,20-trihydroxy-5,8-14-eicosatrienoic acid, 14,15,19- and 14,15,20- trihydroxy-5,8,11-eicosatrienoic acid, and 11,12-dihydroxy-19-oxo- 5,8,14-eicosatrienoic acid. These products were likely formed by ω- and (ω−1)-hydroxylation of 11,12-dihydroxy-5,8,14-eicosatrienoic aic and 14,15-dihydroxy-5,8,11-eicosatrienoic acid, two recently identified metabolites of arachidonic acid in fortified rabbit kidney microsomes. 相似文献