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PubMed2005

Dose-related effects of lauric acid on antropyloroduodenal motility, gastrointestinal hormone release, appetite, and energy intake in healthy men.

We recently reported that intraduodenal infusion of lauric acid (C12) (0.375 kcal/min, 106 mM) stimulates isolated pyloric pressure waves (IPPWs), inhibits antral and duodenal pressure waves (PWs), stimulates release of cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1), and suppresses energy intake and that these effects are much greater than those seen in response to isocaloric decanoic acid (C10) infusion. Administration of C12 was, however, associated with nausea, confounding interpretation of the results. The aim of this study was to evaluate the effects of different intraduodenal doses of C12 on antropyloroduodenal (APD) motility, plasma CCK and GLP-1 concentrations, appetite, and energy intake. Thirteen healthy males were studied on 4 days in double-blind, randomized fashion. APD pressures, plasma CCK and GLP-1 concentrations, and appetite perceptions were measured during 90-min ID infusion of C12 at 0.1 (14 mM), 0.2 (28 mM), or 0.4 (56 mM) kcal/min or saline (control; rate 4 ml/min). Energy intake was determined at a buffet meal immediately following infusion. C12 dose-dependently stimulated IPPWs, decreased antral and duodenal motility, and stimulated secretion of CCK and GLP-1 (r > 0.4, P < 0.05 for all). C12 (0.4 kcal/min) suppressed energy intake compared with control, C12 (0.1 kcal/min), and C12 (0.2 kcal/min) (P < 0.05). These effects were observed in the absence of nausea. In conclusion, intraduodenal C12 dose-dependently modulated APD motility and gastrointestinal hormone release in healthy male subjects, whereas effects on energy intake were only apparent with the highest dose infused (0.4 kcal/min), possibly because only at this dose was modulation of APD motility and gastrointestinal hormone secretion sufficient for a suppressant effect on energy intake.

Adult↗
PubMed1990

Tumor necrosis factor induces necrosis of human carcinoma xenografts in the presence of tricyclodecan-9-yl-xanthogenate and lauric acid.

Recombinant human tumor necrosis factor (rh TNF) when administered intravenously together with the phospholipase C inhibitor tricyclodecan-9-yl-xanthogenate (D609) and lauric acid (C12), leads to the partial regression of various human tumor transplants in athymic mice. Extensive necrosis occurred after a single intravenous infusion, with no detectable side effects. TNF-mediated cytotoxicity was found to be correlated with the depletion of energy in HeLa cells. The activity of rh TNF was enhanced by the absence of glucose, while it was reduced by addition of extraneous ATP. In the presence of rh TNF, D609, and C12, cellular energy metabolism was almost completely switched to glycolysis. Under these conditions the cytocidal activity of rh TNF on HeLa cells was amplified at least 60-fold.

Animals↗
PubMed2002

Enhanced electron transfer and lauric acid hydroxylation by site-directed mutagenesis of CYP119.

CYP119, a cytochrome P450 from a thermophilic organism for which a crystal structure is available, is shown here to hydroxylate lauric acid in a reaction supported by putidaredoxin and putidaredoxin reductase. This fatty acid hydroxylation activity is increased 15-fold by T214V and D77R mutations. The T214V mutation increases the rate by facilitating substrate binding and enhancing the associated spin state change, whereas the D77R mutation improves binding of the heterologous redox partner putidaredoxin to CYP119 and the rate of electron transfer from it to the heme group. A sequence alignment with P450(cam) can, therefore, be used to identify a part of the binding site for putidaredoxin on an unrelated P450 enzyme. This information can be used to engineer by mutagenesis an improved complementarity of the protein-protein interface that results in improved electron transfer from putidaredoxin to the P450 enzyme. As a result, the catalytic activity of the thermo- and barostable CYP119 has been incorporated into a catalytic system that hydroxylates fatty acids.

Amino Acid Sequence↗
PubMed1984

Regiospecific hydroxylation of lauric acid at the (omega-1) position by hepatic and kidney microsomal cytochromes P-450 from rainbow trout.

Microsomes from liver or kidney of untreated rainbow trout hydroxylated lauric acid specifically at the (omega-1) position. Turnover numbers for liver (2.72 min-1) and kidney (14.1 min-1) were decreased seven- and twofold, respectively, following treatment with beta-naphthoflavone. Laurate hydroxylation activity from untreated trout hepatic microsomes was sensitive to inhibition by SKF-525A, but was not sensitive to metyrapone and only partially inhibited by alpha-naphthoflavone. The temperature optimum of laurate (omega-1) hydroxylation in trout liver microsomes was 25-30 degrees C. The Km and Vmax for (omega-1)- hydroxylaurate formation was 50 microM and 1.63 nmol min-1 mg-1, respectively, in liver and 20 microM and 3.95 nmol min-1 mg-1, respectively, in kidney from untreated trout microsomes. (omega-1) Hydroxylation of laurate, in both liver and kidney microsomes, was sensitive to an antibody raised against a previously purified cytochrome P-450 isozyme (LM2) of trout liver microsomes, which has been shown to be active towards aflatoxin B1. Antibody to the major isozyme of cytochrome P-450 ( LM4b , active towards benzo(a)pyrene) induced by beta-naphthoflavone did not inhibit (omega-1) hydroxylation of laurate in microsomes from untreated or beta-naphthoflavone-treated trout.

Animals↗
PubMed1998

Effect of palmitic and lauric acids on the phospholipid bilayer membrane conductivity.

Palmitic acid increased the conductivity of BLM from mitochondrial phospholipids when they were dissolved in a mixture of decane and chlorodecane, and was ineffective when phospholipids were dissolved in decane. Lauric acid produced an increase in the membrane conductivity independently of the phospholipid type in the membrane-forming solutions (mitochondrial phospholipids, asolectin, lecithin with cholesterol) and their solvents (decane or decane with chlorodecane). The results show that discrepancies between published data concerning fatty acid effects on the BLM conductivity may be explained by differences in phospholipids, their solvents and fatty acid used.

Alkanes↗
PubMedDate not supplied

Distribution study of radioactivity in rats after oral administration of the lipido/sterolic extract of Serenoa repens (Permixon) supplemented with [1-14C]-lauric acid, [1-14C]-oleic acid or [4-14C]-beta-sitosterol.

The study carried out on rats given orally the n-hexane lipido/sterolic extract of Serenoa repens (LSESR), supplemented with [14C]-labelled oleic or lauric acids or beta-sitosterol, demonstrated that radioactivity uptake in prostatic tissues shows the highest level in the case of administration of LSESR supplemented with [14C]-labelled oleic acid. This was clearly demonstrated on a rat with an induced fibro-muscular hyperplasia of the prostate and by quantitative measurements of radioactivity. Ratios of radioactivity in tissues compared to plasma show an uptake of radioactivity greater in prostate as compared to other genital organs, i.e. the seminal vesicles or to other organs such as liver.

Administration, Oral↗
PubMed1998

Cytochrome P450-dependent desaturation of lauric acid: isoform selectivity and mechanism of formation of 11-dodecenoic acid.

Cytochrome P450-catalyzed desaturation reactions have been reported infrequently in the literature. Previously, we documented the formation of the terminal olefinic metabolite of valproic acid by various members of the CYP2B and CYP4B sub-families. However, despite the extensive use of fatty acid substrates in drug metabolism studies, other examples of terminal desaturation at non-activated carbon centers are lacking. The goals of the present studies were to determine whether the archetypal P450 substrate, lauric acid (dodecanoic acid; DDA), also undergoes desaturation reactions, identify specific rabbit P450 isoforms which catalyze this reaction and examine its mechanism. A highly sensitive, capillary GC/MS assay was developed to separate and quantitate the trimethylsilyl derivatives of 11-ene-DDA, cis- and trans-10-ene-DDA and cis- and trans-9-ene-DDA. Among all of these potential olefinic metabolites, only 11-ene-DDA was formed at a significant rate by rabbit liver microsomes. The formation of 11-ene-DDA was NADPH-dependent, and was induced markedly by acetone pre-treatment, but not by phenobarbital, rifampin or Arochlor 1254. Studies with seven purified, reconstituted rabbit P450 isoforms showed that the most rapid rates of desaturation were obtained with CYP2E1, CYP4A5/7 and CYP4B1. Non-competitive, intermolecular isotope effect experiments, conducted with [12,12,12-2H3]DDA and [11,11-2H2]DDA, demonstrated further that CYP4B1-mediated terminal desaturation of DDA is initiated by removal of a hydrogen atom from the omega-1 rather than the omega position.

Acetone↗
PubMed2005

Cloning, expression in yeast, and functional characterization of CYP76A4, a novel cytochrome P450 of petunia that catalyzes (omega-1)-hydroxylation of lauric acid.

A cDNA clone of a novel cytochrome P450, CYP76A4, was isolated from Petunia hybrida. The cDNA clone contained an open reading frame (ORF) encoding a predicted 510 amino acid polypeptide. The CYP76A4 cDNA was expressed in yeast Saccharomyces cerevisiae AH22. Recombinant yeast microsomes containing the CYP76A4 hemoprotein were found to catalyze (omega-1)-hydroxylation of lauric acid.

Cloning, Molecular↗
PubMed2000

Equivalence of lauric acid and glycerol monolaurate as inhibitors of signal transduction in Staphylococcus aureus.

Glycerol monolaurate (GML) inhibits the expression of virulence factors in Staphylococus aureus and the induction of vancomycin resistance in Enterococcus faecalis, presumably by blocking signal transduction. Although GML is rapidly hydrolyzed by bacteria, one of the products, lauric acid, has identical inhibitory activity and is metabolized much more slowly. At least four distinct GML-hydrolyzing activities are identified in S. aureus: the secreted Geh lipase, residual supernatant activity in a geh-null mutant strain, a novel membrane-bound esterase, and a cytoplasmic activity.

Chromatography, Thin Layer↗
PubMed1983

Induction of lauric acid hydroxylation and maintenance of cytochrome P-450 content by clofibrate in primary cultures of rat hepatocytes.

The hypolipidemic agent clofibrate at a concentration of 0.5 mM in the culture medium maintained the cytochrome P-450 content of rat hepatocytes for up to 96 hr. This effect was associated with a marked induction of lauric acid hydroxylation whereas little effect was observed on the metabolism of three other cytochrome P-450 dependent mixed function oxidase substrates. The results suggest that clofibrate induces similar form(s) of cytochrome P-450 in cell culture to those observed in vivo and that primary cultures of rat hepatocytes may be useful for studies on both the peroxisomal and microsomal effects of hypolipidemic agents.

Animals↗
PubMed1988

Determination of microsomal lauric acid hydroxylase activity by HPLC with flow-through radiochemical quantitation.

An assay for the microsomal hydroxylation of lauric acid (LA), based on HPLC with flow-through radiochemical detection, has been developed. Conditions were optimized for resolution and quantitation of three microsomal metabolites of LA, one of which has not been reported previously as a metabolite of LA in mammalian microsomal incubations. These products, 12-(omega)-hydroxy-LA, 11-(omega-1)-hydroxy-LA, and a novel metabolite, 10-(omega-2)-hydroxy-LA, were isolated by HPLC and identified by gas chromatography/mass spectrometry. In the presence of NADPH, the formation of all three metabolites was linear with time and microsomal protein concentration. Hydrogen peroxide also supported the microsomal metabolism of LA, although the ratio of metabolites was substantially different than that produced by NADPH-supported microsomes. Several biochemical probes (metyrapone, alpha-naphthoflavone, 2-diethylaminoethyl-2,2-diphenylvalerate hydrochloride, and 10-undecynoic acid) were used to dissociate the three LA hydroxylase activities. These experiments suggest that the site-specific hydroxylation [omega-, (omega-1)-, (omega-2)-] of LA may be catalyzed by different isozymes of cytochrome P-450.

Animals↗
PubMed1987

Isolation, complementary DNA sequence, and regulation of rat hepatic lauric acid omega-hydroxylase (cytochrome P-450LA omega). Identification of a new cytochrome P-450 gene family.

Lauric acid omega-hydroxylase (cytochrome P-450LA omega) was purified from livers of rats that had been given the hypolipidemic drug clofibrate. Immunoblot analysis with anti-cytochrome P-450LA omega antibody revealed the presence of two clofibrate-induced cytochrome P-450 proteins in both liver and kidney. This antibody was used to screen a lambda gt11 expression library constructed from liver mRNA isolated from rats given clofibrate. The clone, pP-450LA omega, was isolated and found to contain 2062 base pairs with an open reading frame of 509 amino acids (Mr 58,222). The pP-450LA omega cDNA insert was placed in the yeast expression vector pAAH5, and the resultant plasmid expressed a protein of the same size and activity as cytochrome P-450LA omega. The mechanism of the regulation of the cytochrome P-450LA omega gene by hypolipidemic agents was examined. The rate of cytochrome P-450LA omega gene transcription was increased as early as 1 h after administration of clofibrate, and this increase was followed by an elevation of cytochrome P-450LA omega mRNA, immunochemically detectable protein, and cytochrome P-450LA omega activity. In contrast, no increase in transcriptional activity was detected after clofibrate administration for the cytochrome P-450PCN or P-450b/e genes. The cytochrome P-450LA omega has several structural features in common with other cytochrome P-450s, including a conserved cysteine-containing heme-binding fifth ligand fragment and a hydrophobic amino terminus. Overall, cytochrome P-450LA omega shared less than 35% cDNA nucleotide and amino acid similarity with cytochromes P-450c, P-450d, P-450e, and P-450PCN, indicating that it is a member of a new cytochrome P-450 gene family. Southern blot analysis indicates that this family contains two or three genes.

Amino Acid Sequence↗
PubMed1985

Structure-dependent induction of bilirubin glucuronidation and lauric acid 12-hydroxylation by arylcarboxylic acids chemically related to clofibrate.

The inductive potency of carboxylic acids, structurally related to clofibrate, on bilirubin UDPglucuronosyltransferase was investigated in the rat. For this purpose, structure-induction relationships were established using ten different arylcarboxylic or chlorophenoxycarboxylic acids. 4'-Chlorophenoxyacetic, -propionic and -isobutyric (clofibric) acids progressively increased hepatic glucuronidation of bilirubin (17%, 43%, 60% greater than controls, respectively) after a 5-day treatment in rat (100 mg/kg per day). 2-Phenylpropionic acid also enhanced bilirubin UDPglucuronosyltransferase activity (50%) in contrast to phenylacetic acid. The other compounds did not, or only slightly, affect this parameter. These results indicate that specific structural features are required for the induction property. Moreover, a good correlation (r = 0.962) was found between the extent of induction and the physiochemical descriptors which characterize the electronic state of the molecules, when analysed by multidimensional regression. Fluorescence polarization revealed that the compounds tested, especially clofibric acid, did not affect, in vivo or in vitro, the anisotropy of two different probes embedded in the microsomal membranes. Finally, since the interaction of the carboxylic acids with the membranes did not modify the latency state of bilirubin UDPglucuronosyltransferase, it was concluded that the increase in enzyme activity was due more to a real induction than to activation of bilirubin UDPglucuronosyltransferase. A close linkage was established between bilirubin UDPglucuronosyltransferase induction and that of cytochrome P-452, as shown by enhanced omega-oxidation of lauric acid. This led to the hypothesis that both processes could be under coordinate regulation and mediated by a molecular interaction depending on the physicochemical properties of the carboxylic acids.

Animals↗
PubMed1999

Encoding of a cytochrome P450-dependent lauric acid monooxygenase by CYP703A1 specifically expressed in the floral buds of petunia hybrida.

The cDNA clone of novel cytochrome P450 CYP703A1 from petunia floral buds was isolated by RT-PCR. The nucleotide sequences of this cDNA clone contained the open reading frame that has been predicted to encode polypeptides consisting of 539 amino acid residues. A significantly high level of the transcript of the cyp703A1 gene was found in the early stage of petunia flower buds, but not in the leaves, stems and roots. The 1041bp 5'-flanking sequences of the cyp703A1 gene contained the conserved motifs of ATHB-1, AGAMOUS, MYB.Ph3, P and SBF-1 binding boxes. CYP703A1 cDNA was expressed in yeast Saccharomyces cerevisiae AH22 cells under the control of an alcohol dehydrogenase I promoter and terminator. The recombinant yeast microsomes containing the CYP703A1 hemoprotein were found to metabolize lauric acid. Based on these results, CYP703A1 was specifically expressed in the early stage of flower development and appeared to participate in the monooxygenation of fatty acids.

Alcohol Oxidoreductases↗
PubMed2000

CYP78A1 preferentially expressed in developing inflorescences of Zea mays encoded a cytochrome P450-dependent lauric acid 12-monooxygenase.

Cytochrome P450 (P450 or CYP) monooxygenases play an important role in the oxidation of a number of lipophilic substrates including secondary metabolites in higher plants. Larkin reported that CYP78A1 was preferentially expressed in developing inflorescences of Zea mays (Larkin, Plant Mol. Biol. 25: 343-353, 1994). However, the enzymatic function of CYP78A1 hasn't been clarified yet. To characterized the enzymatic activity of CYP78A1, in this study, CYP78A1 cDNA and tobacco or yeast NADPH-cytochrome P450 oxidoreductase (P450 reductase) was expressed in the yeast Saccharomyces cerevisiae AH22 cells under the control of alcohol dehydrogenase promoter I and terminator. The reduced CO-difference spectrum of a microsomal fraction prepared from the transformed yeast cells expressing CYP78A1 and yeast P450 reductase showed a peak at 449 nm. Based on the spectrum, the content of a P450 molecule was estimated to be 45 pmol P450 equivalent/ mg of protein in the microsomal fraction. The recombinant yeast microsomes containing CYP78A1 and yeast P450 reductase were found to catalyze 12-monooxygenation of lauric acid. Based on these results, CYP78A1 preferentially expressed in developing inflorescences of Zea mays appeared to have participated in the monooxygenation of fatty acids.

Catalysis↗
PubMed1995

Human liver lauric acid hydroxylase activities.

Nine male and five female human liver microsomal sample were examined for laurate 11- and 12-hydroxylase activities. The mean specific activities for the 11- and 12-hydroxylation reactions were 0.78 +/- 0.33 and 1.07 +/- 0.12 nmol/min/mg protein, respectively. Antibody inhibition experiments, using a polyclonal antibody to a cytochrome P450 (P450) isolated from diethylhexyl phthalate-treated rats, which recognizes forms P4504A1, P4504A2, and P4504A3 of the rate, inhibited the 12-hydroxylase activity by 65%, but did not affect 11-hydroxylase activity. Western-blot analyses of the 14 human liver microsomal samples identified one major protein band at 52 kDa that comigrated with human form 4A11. A correlation coefficient of only 0.19 was calculated when comparing laurate 12-hydroxylase activities and the densitometric values of the immunochemically reactive protein bands in the human liver microsomal samples, which strongly suggests that additional P450 forms also support the 12-hydroxylation of lauric acid. Laurate 11-hydroxylase activity was inhibited by diethyldithiocarbamate, an inhibitor of P4502E1-mediated reactions, and by chlorzoxazone, a P4502E1 substrate. A comparison of laurate 11-hydroxylase activities with densitometric values of the P4502E1 protein bands indicated a strong correlation existed (0.82). An analysis of microsomal samples containing expressed human forms P4501A2, P4502A6, P4502C8, P4502C9, P4502D6, P4502E1, and P4503A4 showed that only form P4502E1 supported the 11-hydroxylation reaction.

Adolescent↗
PubMedDate not supplied

The effect of hypolipidemic agents on the hepatic microsomal drug-metabolizing enzyme system of the rat. Induction of cytochrome(s) P-450 with specificity toward terminal hydroxylation of lauric acid.

The effect of chronic dietary administration of the hypolipidemic agents, clofibrate, methylclofenapate, fenofibrate, and tibric acid, on the hepatic drug-metabolizing enzyme system of the albino rat has been studied. Each compound caused dose-dependent increase in liver size and cytochrome P-450 (methylclofenapate = fenofibrate = tibric acid greater than clofibrate). NADPH-cytochrome c reductase activity was increased only after clofibrate and methylclofenapate treatment. There was no overall increase in the metabolism of a number of commonly used model substrates in parallel with the cytochrome P-450 induction. Aminopyrine and ethoxyresorufin dealkylation, biphenyl 4-hydroxylation, testosterone 16 alpha-hydroxylation, and o-aminophenol and chloramphenicol glucuronidation showed no change or inhibition, whereas ethoxycoumarin and phenacetin dealkylation and testosterone 6 beta-hydroxylation were increased (only up to 2-fold). Using clofibrate as a representative of this class of pharmacological agent, the enzymatic changes were essentially reversed within 6 days after removal of drug from the diet. Clofibrate administration also increased liver size and, to a lesser extent, hepatic cytochrome P-450 content in the albino (CD-1) mouse but had no effect in the marmoset monkey. In the rat, clofibrate administration specifically increased the hepatic microsomal omega-hydroxylation of lauric acid approximately 28-fold, which contrasted with the specific increase in (omega - 1)-hydroxylation caused by phenobarbital administration. The specific increase in microsomal cytochrome P-450-mediated omega-oxidation of a medium length, straight chain, saturated fatty acid is similar to the documented increase in peroxisomal and mitochondrial fatty acid beta-oxidation caused by administration of hypolipidemic agents.

Animals↗
PubMed2004

Adsorption behavior of lauric acid at heptane/water interface as studied by second harmonic generation spectroscopy and interfacial tensiometry.

Interfacial tensiometry and second harmonic generation (SHG) spectroscopy were applied to examine the adsorption behavior of lauric acid (LA) at a heptane/water interface. From interfacial tensiometry measurements, the adsorption kinetics of LA was revealed to be diffusion-controlled, and the adsorption constant of LA was estimated to be 9.6 x 10(4) M(-1). The adsorption isotherms obtained by SHG measurements were analyzed by taking account of both the molecular orientation of LA at the interface and a surface electric field generated by the adsorbed LA layer. It was confirmed that the carboxylic groups of adsorbed LA molecules were well ordered at the heptane/water interface and the orientation of the carboxylate group was invariant during the adsorption process.

Journal Article↗