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PubMedDate not supplied

Extraction of omega- and omega-1-hydroxylauric acids with ethyl acetate results in formation of acetoxy products.

In studies of the regiospecific metabolism of lauric acid by monooxygenase enzymes, incubation medium from the reaction of [14C] lauric acid and microsomes is routinely acidified and extracted with ethyl ether. Separation of products by HPLC shows the formation of omega(12)- and omega-1(11)-hydroxylauric acids by rat liver microsomes. In a comparison of several extraction solvents, we observed that the extraction of incubation media with ethyl acetate alone was associated with the appearance of a major new metabolite peak concomitant with loss of the 12- and 11-hydroxylaurate peaks by 62 and 23%, respectively. No difference was observed between extraction procedures in the per cent recovery of radiolabel. Similar results were observed with extraction of lauric acid metabolites formed by fish liver microsomes. Acidification of the incubation media prior to ethyl acetate extraction prevented formation of the new metabolite peak. In experiments to identify the new metabolite(s), 11- and 12-hydroxylaurate products formed by rat liver microsomes were acetylated and found to show an HPLC retention time similar to that of the unknown metabolite peak formed with ethyl acetate extraction. Mass spectrometric analysis further showed that the methyl esters of 11- and 12-acetoxylauric acids were very similar to that of the methyl ester derivative of the unknown metabolite fraction. Thus, data indicate that the acetoxy derivatives of 11- and 12-hydroxylauric acids were formed by direct reaction of ethyl acetate with the laurate products formed by microsomal monooxygenase enzymes. This extraction procedure can produce a major shift in the amount and ratio of omega- and omega-1-hydroxylaurates measured in the incubation media.

Acetates↗
PubMedDate not supplied

Mechanism of azoreduction of dimethylaminoazobenzene by rat liver NADPH-cytochrome P-450 reductase and partially purified cytochrome P-450. Oxygen and carbon monoxide sensitivity and stimulation by FAD and FMN.

We have reported that the hepatocarcinogen dimethylaminoazobenzene (DAB) is reduced by rat liver microsomes in an oxygen- and carbon monoxide-insensitive manner and that activity is induced by clofibrate but no other recognized inducers of cytochrome P-450 activity. In the present study we have shown that the reaction proceeds in a partially purified reconstituted cytochrome P-450 system as well as with purified NADPH-cytochrome P-450 reductase alone. In the latter system, activity is totally inhibited in air whereas the former system is active in air as well as in a carbon monoxide atmosphere. Although clofibrate induces both DAB azoreductase and laurate hydroxylase activities, the suicide substrate 10-undecynoic acid blocks the latter but not the former, implying catalysis by distinct enzymes. FAD and FMN stimulate DAB azoreduction 40-50-fold by both NADPH-cytochrome P-450 reductase alone and by the reconstituted cytochrome P-450 system. However, it was shown that these flavins facilitate electron flow to DAB only from reductase and not from cytochrome P-450. The fact that the reconstituted system, which contains NADPH-cytochrome P-450 reductase, is oxygen insensitive suggests that there is an obligatory electron flow through cytochrome P-450 to DAB, bypassing the oxygen-sensitive step.

Animals↗
PubMed1987

Biochemical characterization of hepatic microsomal leukotriene B4 hydroxylases.

omega-Hydroxylation of leukotriene B4 (LTB4) has been reported in human and rodent polymorphonuclear leukocytes; preliminary information indicates that this metabolism is cytochrome P-450 dependent. Therefore, these studies were initiated to characterize the cytochrome P-450-dependent metabolism of LTB4 in other tissues. LTB4 was metabolized by rat hepatic microsomes to two products, 20-hydroxy(omega)-LTB4 and 19-hydroxy(omega-1)-LTB4. The formation of these metabolites was both oxygen and NADPH dependent indicating that a monooxygenase(s) was responsible for these reactions. The apparent Km and Vmax for LTB4 omega-hydroxylase were 40.28 microM and 1202 pmol/min/mg of protein, respectively. In contrast, the apparent Km and Vmax for LTB4 (omega-1)-hydroxylase were 61.52 microM and 73.50 pmol/min/mg of protein, respectively. Both LTB4 omega- and (omega-1)-hydroxylases were inhibited by metyrapone in a concentration-dependent fashion. However, SK&F 525A inhibited LTB4 (omega-1)- but not omega-hydroxylase. In contrast, alpha-naphthoflavone decreased LTB4 omega- but not (omega-1)-hydroxylase activities. The differences in the Km apparent for substrate as well as the differential inhibition by inhibitors of cytochrome P-450 suggest that the omega- and (omega-1)-hydroxylations of LTB4 in hepatic microsomes are mediated by different isozymes of P-450. Furthermore, several additional characteristics of LTB4 hydroxylases indicate that these isozymes of P-450 may be different from those which catalyze similar reactions on medium-chain fatty acids, such as laurate and prostaglandins.

Animals↗
PubMed1978

omega- and (omega--1)-hydroxylation of fatty acids by frog liver microsomes. Substrate specificity and other properties.

Frog liver microsomes catalyzed the hydroxylation of various saturated fatty acids whose chain lengths were from 8 to 18 carbon atoms into the corresponding omega- and (omega--1)-hydroxy derivatives. In addition, small amounts of the dicarboxylic acids and (omega--1)-keto acids were also formed from all the fatty acids. The relative activity of the hydroxylase with the substrates was as follows: C13(100), C12(98), C14(88), C10(62), C16(34), C18(29), and C8(8). The percentage of omega-hydroxy derivative relative to the (omega--1)-isomer increased with increasing carbon chain length of the fatty acid substrate. Oleate, linoleate and linolenate were also tested and found to be at least as active their saturated analog (stearate). Both NADPH and O2 were required for hydroxylase activity. The apparent Km for NADPH was 3.7 . 10(-5) M, and NADH had very little effect. The apparent Km value for laurate was 1.5 . 10(-5) M. The hydroxylating system was about 50% inhibited by 10 mM KCN and 81% inhibited by CO at a CO : O2 ratio of 4.0. In contrast, NaN3 showed no effect on hydroxylation.

Animals↗
PubMed1988

Complete structural determination of lipopolysaccharide obtained from deep rough mutant of Escherichia coli. Purification by high performance liquid chromatography and direct analysis by plasma desorption mass spectrometry.

Lipopolysaccharide (LPS) extracted from the deep rough mutant of Escherichia coli D31m4 was disaggregated with 0.1 M EDTA, pH 7.0, and fractionated on a diethylaminoethyl-cellulose column to yield the biphosphate form of LPS. After methylation, the derivative was purified by reverse-phase high performance liquid chromatography using a C18-bonded silica cartridge. A linear gradient of 50-100% isopropyl alcohol/water (93:7, v/v) in acetonitrile/water (93:7, v/v) was used over a period of 60 min. The derivatized LPS showed a single major peak by high performance liquid chromatography, and this hexamethyl hexaacyl LPS was recovered and subjected to chemical analysis, plasma desorption mass spectrometry, and nuclear magnetic resonance (NMR) spectroscopy. Chemical analysis of the purified hexamethyl LPS quantitated certain key chemical compositions. Plasma desorption mass spectrometry showed a molecular ion (M + CH2 + Na)+ at m/z 2360, which established the molecular formula and Mr to be C116H214N2O39P2 and 2323, respectively. Thus, it contained two each of glucosamine, 2-keto-3-deoxyoctonate, and phosphate; four beta-hydroxymyristates; one laurate; and one myristate. NMR spectroscopy confirmed the locations of the four ester-linked fatty acyl groups. Based on these results and the known structure of free lipid A, the complete structure of the deep-rough chemotype LPS from E. coli can now be presented with confidence. This is the first report of a successful purification to homogeneity and the characterization of the simplest of the LPS at the intact level. This study shows that the natural distribution of the lipid A moiety of LPS from E. coli D31m4 is hexaacyl/pentaacyl in a molar ratio of greater than 90:less than 10. Acid hydrolysis of LPS causes the formation of the lower homologues of the free lipid A.

Chemical Fractionation↗
PubMed1988

Myristic acid binding to human serum albumin investigated by dialytic exchange rate.

Dialysis rate determinations of several fatty acids in the absence of albumin revealed that the myristate anion, like that of laurate, in aqueous solution, pH 7.5, is present as a monomer anion when the concentration is below 25 microM. Palmitate and oleate solutions, on the other hand, show a tendency to aggregation even at concentrations below 0.5 microM. Multiple binding of myristate to human serum albumin in phosphate buffer, at pH 7.5, 37 degrees C, was investigated by exchange of 14C-labeled myristate across a dialysis membrane under conditions of binding equilibrium. A binding isotherm was established by least squares fitting of the stoichiometric binding constants in the stepwise binding equation to the experimental data. The best-fit solution was supplemented with 30 acceptable solutions within a probability limit of 0.95. A concept of one or two distinct high-affinity sites for binding of fatty acids could not be verified; the observations allow a variety of binding mechanisms ranging from cooperativity of the first two myristates to a model with four equal and independent sites.

Dialysis↗
PubMed1986

Purification and characterization of two forms of cytochrome P-450 from rat kidney cortex microsomes.

Two forms of cytochrome P-450 (P-450), designated P-450 k-1 and P-450 k-2, have been purified about 100-fold from rat kidney cortex microsomes. P-450 k-1 and P-450 k-2 have monomeric molecular weights of 51,500 and 52,000, respectively, on sodium dodecyl sulfate(SDS)-polyacrylamide gel electrophoresis. Absolute spectra of the oxidized forms indicate that P-450 k-1 is largely in the low-spin state and partly in the high-spin state, and that P-450 k-2 is essentially all in the former. The absorption maxima in reduced carbon monoxide difference spectra are at 450.5 and 451 nm with P-450 k-1 and P-450 k-2, respectively. The two P-450s catalyze the omega- and (omega-1)-hydroxylation of fatty acids such as caprate, laurate, myristate, and palmitate, although P-450 k-1 exhibits a higher specific activity with all fatty acids tested. In addition, P-450 k-1 is capable of hydroxylating prostaglandin (PG) A1 and A2 at the omega-position, whereas P-450 k-2 has no activity toward PGs. These activities are all stimulated by addition of cytochrome b5. The two P-450s give different peptide map patterns when partially digested with Staphylococcus aureus V8 protease or papain.

Animals↗
PubMed1986

A comparison of the effect of Lipo PGE1 and other related compounds on experimental peripheral arterial occlusive disease in rats.

The effect of Lipo PGE1 (prostaglandin E1 incorporated in lipid microspheres) on laurate-induced peripheral arterial occlusive disease in rats was evaluated and compared with that of other related compounds. Lipo PGE1 showed a potent inhibitory effect on the progression of lesions in this model, but Lipo PGA1 had no such effect. Moreover, the effect of Lipo PGE1 was more potent than that of PGE1 X CD (cyclodextrin clathrated PGE1) and PGE1 on this model. These results suggest that incorporation of PGE1 into soybean oil microspheres might exert a more potent effect by facilitating drug delivery to the lesions in this model. It would appear that Lipo PGE1 is suitable for clinical use in peripheral vascular disorders.

Alprostadil↗
PubMed1979

Phosphoenolpyruvate carboxylase of Escherichia coli. Effect of proteolytic modification on the catalytic and regulatory propties.

Phosphoenolpyruvate carboxylase from Escherichia coli W was treated with ten proteases, and the effects of the treatments on the enzyme activity and sensitivity to effectors were investigated. Proteases such as trypsin, alpha-chymotrypsin, papain, and subtilisin inactivated the enzyme, whereas elastase, carboxypeptidase Y and leucine aminopeptidase had no effect on the enzyme activity. Elastase and carboxypeptidase Y, however, inactivated the enzyme in the presence of 1 m urea. Subtilisin and alpha-chymotrypsin caused not only inactivation of the enzyme but also a significant desensitization to the effectors. DL-Phospholactate, a potent competitive inhibitor, markedly protected the enzyme from inactivation by subtilisin but did not protect it from desensitization to the effectors. Acetyl-CoA, fructose 1, 6-bisphosphate, and GTP-the allosteric activators--protected the enzyme from subtilisin inactivation, while laurate, the other allosteric activator, accelerated the inactivation. These activators did not protect the enzyme from desensitization to themselves. In contrast, modification with subtilisin in the present of l-aspartate, the allosteric inhibitor, caused an apparent transient activation of the enzyme. The enzyme modified in the presence of L-aspartate retained its sensitivity to L-aspartate, but the sensitivities to the other effectors were reduced to about one-half their initial values. Based on these results, a possible mode of desensitization of the enzyme by subtilisin modification and the possible existence of a multiplicity of conformational states of the enzyme, induced upon binding with the various effectors, are discussed.

Carboxy-Lyases↗
PubMed1985

Uptake of fatty acids by isolated heart myocytes.

An adult rat heart myocyte preparation was used to study the uptake and metabolism of the 1-14C-labelled fatty acids decanoate, laurate, myristate, and palmitate. Metabolism was saturable, but free fatty acid accumulation was not. Use of metabolic inhibitors indicated that metabolism and not uptake was rate limiting at 37 degrees C and that uptake was energy dependent. Competition was demonstrated for the metabolic pathways but not for free fatty acid accumulation. The activation energy for uptake decreased with increasing fatty acid chain length. A diffusion mechanism for long chain fatty acid uptake is proposed.

Animals↗
PubMed1985

Monophosphoryl lipid A obtained from lipopolysaccharides of Salmonella minnesota R595. Purification of the dimethyl derivative by high performance liquid chromatography and complete structural determination.

The monophosphoryl lipid A (MLA) obtained from the lipopolysaccharides of Salmonella minnesota R595 was fractionated on a silicic acid column to yield the heptaacyl, hexaacyl, and pentaacyl MLA. Each of these MLAs was methylated with diazomethane to yield the dimethyl derivative and purified to homogeneity by reverse-phase high performance liquid chromatography. The molecular ions obtained by positive ion fast atom bombardment mass spectrometry of purified dimethyl heptaacyl MLA allowed us to establish the molecular formula and Mr of C112H211N2O23P and 1983.3, respectively. Cleavage at the glycosidic linkage yielded an oxonium ion of mass 1115, which showed that the distal sugar unit contained one phosphate (dimethyl), two hydroxymyristates, one laurate, and one myristate, while the reducing sugar unit contained two hydroxymyristates and one palmitate. By utilizing two-dimensional NMR spectroscopy, we were able to assign all of the protons of dimethyl heptaacyl MLA. This assignment included the beta protons of the three acyloxyacyl groups. A substantial downfield shift of the protons at the 3- and 3' -carbons was observed, which indicated that these two positions are occupied by ester groups. Fast atom bombardment mass spectral analysis of the hexaacyl and pentaacyl MLAs showed that these structures were identical to the previously designated TLC-3 and TLC-5 fractions, respectively, from Salmonella typhimurium. From this study, the complete structures of the MLA series found in the LPS of S. minnesota can now be described.

Chemical Phenomena↗
PubMed1985

Effect of cilostazol, a new antithrombotic drug, on an experimental model of peripheral circulation insufficiency.

Acute arterial obstruction in hind limb was experimentally induced by intra-arterial injection of sodium laurate saline solution in mongrel dogs, and the inhibitory action of cilostazol (6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]- 3,4-dihydro-2(1H)-quinolinone, OPC-13013) on ulcer formation was studied. Cilostazol at oral doses of 10 and 30 mg/kg inhibited ulcer development. Cilostazol inhibited decrease in skin temperature in obstructed hindlimbs in a dose-dependent manner. Cilostazol also inhibited increase of plasma aldolase, creatine phosphokinase and glutamic oxalacetic transaminase activities, presumably due to necrosis of the skeletal muscle.

Animals↗
PubMed1969

Binding of long-chain fatty acids to bovine serum albumin.

We have studied the binding of long-chain free fatty acids (FFA) to crystalline bovine serum albumin (BSA) that had been extracted with charcoal to remove endogenous fatty acids. The data were analyzed in terms of a model consisting of six high-energy binding sites and a large number of weak binding sites. The high-energy sites were resolved into two distinct classes, each containing three sites. At 37 degrees C and pH 7.4, k'(1) (the apparent association constant of a class of binding sites) was about 10(6) m(-1) for binding to the three primary sites, and k'(2) was about 10(5) m(-1) for binding to the three secondary sites. The number of weak (tertiary) sites was estimated to be 63 with a k'(3) of 10(3) m(-1). In general, palmitate and palmitoleate were bound more tightly than oleate, linoleate, stearate, or myristate, and much more tightly than laurate. The association of palmitate with human and rabbit albumin also was analyzed in terms of this model. Palmitate was bound less firmly by human or rabbit albumin than by BSA. Palmitate binding to BSA was dependent upon the pH and temperature of the incubation medium. Long-chain hydrocarbons that did not contain a free carboxyl group (methyl palmitate, cetyl alcohol, and hexadecane) were bound to a limited extent and weakly. The presence of positively charged protein sites and native protein tertiary structure were required for maximal binding of palmitate to BSA. Of nine other proteins tested, only -lactoglobulin exhibited a significant capacity to bind palmitate.

Animals↗
PubMed1969

Fatty liver produced by dietary deficiencies: its pathogenesis and potentiation by ethanol.

In a study of the pathogenesis of hepatic fat accumulation under experimental conditions mimicking chronic alcoholism, rats were fed a low-fat diet, deficient in amino acids and choline, containing either ethanol or isocaloric amounts of carbohydrate. Dietary deficiencies alone produced a moderately fatty liver after 24 days. The combination of ethanol and dietary deficiencies resulted in enhanced lipid accumulation, which was apparent after only 11 days. In an investigation of the origin of hepatic triglyceride fatty acids, the experiment was repeated after the adipose lipids had been marked by the feeding of oils containing characteristic fatty acids (linseed oil, containing linolenate, or coconut oil, containing laurate and myristate). In all animals, the fatty acid composition of the hepatic triglycerides differed markedly from that of adipose tissue; it had a larger percentage of endogenously synthesized fatty acids and a five times smaller percentage of the marker fatty acids. In addition, ethanol feeding resulted in a greater retention of the marker fatty acids in the adipose tissue. Thus, the deposition of hepatic triglycerides produced by the feeding of deficient diets is markedly potentiated by ethanol; the triglyceride fatty acids accumulated under these conditions appear to originate, for the most part, not from mobilization of depot fat, but from endogenous synthesis.

Adipose Tissue↗
PubMedDate not supplied

Etofenamate fatty acid asters. An example of a new route of drug metabolism.

Etofenamate [2-(2-hydroxyethoxy)ethyl-N-(alpha, alpha, alpha-trifluoro-m-tolyl)-anthranilate] was administered to dogs by the oral route. Minor amounts of etofenamate (Eto) and its glucuronide were found in urine and feces. The main portion of metabolites was eliminated as flufenamic acid (Flu) and hydroxy derivatives of Eto and Flu. Furthermore, a highly lipophilic fraction was isolated (extraction and TLC) and further separated into several compounds (HPLC, GLC). These metabolites were identified as Eto oleate, palmitate, linoleate, stearate, palmitoleate, myristate, and laurate by NMR and MS. The structures were confirmed by comparison with authentic material. The conjugation of etofenamate with fatty acids is an example of a new route of drug metabolism.

Administration, Oral↗
PubMedDate not supplied

In vitro metabolism of mono-2-ethylhexyl phthalate by microsomal enzymes. Similarity to omega- and (omega-1) oxidation of fatty acids.

Mono-2-ethylhexyl pthalate (MEHP) is oxidized to omega-, omega-1-, and omega-2-hydroxylation products as well as (very slightly) to a dicarboxylic acid by washed microsomes from rat liver and kidney, and rabbit but not rat lung. The reactions involve molecular oxygen, are strongly inhibited by carbon monoxide and oxidized cytochrome c, and NADPH is preferred over NADH. Piperonyl butoxide inhibits hydroxylation of MEHP, but clofibrate does not. The differential effects of inducers (phenobarbital and clofibrate) and inhibitors (sodium laurate, n-decane, metyrapone) on terminal and subterminal hydroxylation as well as differences in apparent Km for the two suggest that rat liver contains at least two different MEHP hydroxylases. Comparisons of tissue distribution, susceptibility to inhibitors, and induction properties suggest that the hydroxylation of MEHP is more likely to be mediated by the P-450 isozymes associated with omega- and (omega-1)-hydroxylation of fatty acids than with those that utilize hydrocarbons as substrates.

Animals↗
PubMed1984

A study of the activity of soft soaps prepared from a homologous series of saturated fatty acids against cells of Escherichia coli NCTC 9001.

Soaps were prepared by direct neutralization of a homologous series of fatty acids with potassium hydroxide, the acids used being lauric, myristic palmitic and stearic acids. The antibacterial activity of these soaps were studied using Escherichia coli as the test organism. From the various phenomena examined it can be concluded that all the soaps used had a measure of antibacterial activity, the order of this activity being myristate, laurate, palmitate, and stearate. The antibacterial activity of both the palmitate and the stearate can only be described as marginal.

Acriflavine↗
PubMed1983

[The effect of cholesterol and the nature of dietary fatty acids on the activities of some microsomal monooxygenases in the rat liver].

For 9 weeks, 2-month old male rats were fed diets containing 0 or 2% cholesterol and 15% corn oil or coconut oil (2 x 2 factorial experiment). The activity of several cytochrome P450-dependent monooxygenases from liver microsomes was measured. Dietary cholesterol increased liver weight; this effect was more marked in rats fed unsaturated fat than in those fed saturated fat. The activity of NADPH-cytochrome c reductase and cytochrome b5 contents was also enhanced by dietary cholesterol. The type of dietary fat mainly affected the activities of NADPH-cytochrome c reductase and aminopyrine demethylase. The latter was 34% higher in rats fed corn oil than in rats fed coconut oil. In contrast, the activities of aniline hydroxylase and laurate hydroxylase were not modified by dietary fat. Briefly, the dietary factors studied affected the activity of microsomal monooxygenases differently.

Aminopyrine N-Demethylase↗