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PubMed2000

Topical revitalization of body skin.

Topical treatments for the body are beneficial for photoageing as well as for specific disease processes, such as scars or striae. Every patient should topically apply photoprotectants in order to prevent photodamage to the skin. Tretinoin can improve body skin and has a documented use in striae. Alpha-hydroxy acids can restore body skin when used on a regular basis. Antioxidants may be of benefit. Scars can be improved with a variety of topically applied agents ranging from silicone gel sheeting to super-potent topical steroids. Chemical peeling for the body can improve the skin with the use of alpha- or beta-hydroxy acids. While topical therapy can improve body skin, adjunctive surgical therapy may be needed to correct body skin disorders or concerns fully.

Adipose Tissue↗
PubMed1989

Oxidation of methionine and 2-hydroxy 4-methylthiobutanoic acid stereoisomers in chicken tissues.

Oxidation of DL-2-hydroxy 4-methylthiobutanoic acid (DL-HMB), DL-methionine (DL-MET) and L-methionine (L-MET) in chicken tissue homogenates was compared using 1-14C-labelled tracers. The pattern of oxidation of the substrates was similar at both low (0.7 mM) and high (20 mM) concentrations. The rate of conversion to 2-keto 4-methylthiobutanoic acid (KMB) was highest for DL-MET and lowest for L-MET in kidney, liver and intestinal mucosa. In breast muscle, rates for DL-MET and L-MET were similar at 0.7 mM, but DL-HMB showed the highest rate at 20 mM. Kidney contained the highest specific activity for oxidation of all three substrates. Raising the pH of liver and kidney homogenates from 7.5 to 8.6 increased the oxidation of DL-MET, exclusively. Experiments with inhibitors of D-2-hydroxy acid dehydrogenase (EC 1.1.99.6) and L-2-hydroxy acid oxidase (EC 1.1.3.15) suggested that D- and L-HMB were stereospecifically oxidized by the enzymes. KMB stimulated L-MET oxidation in kidney yet inhibited L-MET oxidation in liver homogenates. The effect of KMB on DL-MET and DL-HMB oxidation also varied between tissues. Amino-oxyacetate inhibited L-MET oxidation completely and DL-MET and DL-HMB oxidation almost completely in both kidney and liver. L-Cycloserine was less potent than amino-oxyacetate and decreased L-MET oxidation more in kidney than in liver. It can be calculated from the results that, at low substrate concentrations, the liver contributes principally to the whole body oxidation of both DL-HMB and DL-MET. At high (greater than physiological) concentrations, DL-HMB would be oxidized principally in skeletal muscle. At all concentrations, L-MET would be converted to KMB mainly in the muscle.

Animal Nutritional Physiological Phenomena↗
PubMed2004

A new synthesis of indole 5-carboxylic acids and 6-hydroxy-indole-5-carboxylic acids in the preparation of an o-hydroxylated metabolite of vilazodone.

A major metabolite of the potential antidepressant vilazodone formed in rat, dog, monkey and human liver microsomes is the 5-cyano-6-hydroxy-1H-indole derivative. For the construction of the salicyl-like substituted indole we adapted a synthesis of carmoxirole using Japp-Klingemann type Fischer-indole synthesis protocols. Functional group interconversion of carboxylic acid via carboxamide into cyanide was performed with methanesulfonic acid chloride.

Antidepressive Agents↗
PubMed1992

A comparative study of gluconolactone versus benzoyl peroxide in the treatment of acne.

Alpha hydroxy acids (AHA's) or "fruit acids" are a special group of organic acids found in many natural foods. They have been described in the literature for the treatment of a number of conditions in which abnormal keratinization consistently contributes to pathogenesis. These include the icthyoses, warts, psoriasis, eczema and acne. We have performed a double-blind clinical trial on 150 patients to evaluate the efficacy and skin tolerance of the alpha hydroxy acid gluconolactone 14% in solution (Nuvoderm lotion) in the treatment of mild to moderate acne when compared with its vehicle (placebo) and 5% benzoyl peroxide lotion. The results of this study showed that both gluconolactone and benzoyl peroxide had a significant effect in improving patients' acne by reducing the number of lesions (inflamed and non-inflamed). Furthermore, fewer side-effects were experienced by patients treated with gluconolactone when compared with benzoyl peroxide.

Acne Vulgaris↗
PubMed2002

Petrobactin, a photoreactive siderophore produced by the oil-degrading marine bacterium Marinobacter hydrocarbonoclasticus.

Petrobactin is a bis-catecholate, alpha-hydroxy acid siderophore produced by the oil-degrading marine bacterium Marinobacter hydrocarbonoclasticus. The Fe(III)-complexed form of petrobactin is photoreactive in natural sunlight, mediated by the Fe(III)-citrate moiety. The reaction results in decarboxylation of the petrobactin ligand and reduction of Fe(III) to Fe(II). This report is one of the first to show the photoreactivity of Fe(III)-siderophores mediated by the ferric ion-alpha-hydroxy acid group. The demonstration of light-mediated decarboxylation of an Fe(III)-siderophore complex raises questions about a possible functional role for photoreactivity in siderophore-mediated iron uptake.

Benzamides↗
PubMed2005

Systematic evaluation of the conformational properties of aliphatic omega-methoxy methyl esters.

[structure: see text] A systematic conformational study of omega-methoxy methyl esters, CH(3)O-(CH2)n-COO-CH3 with n = 3 and 4, has been performed using quantum mechanical calculations at the MP2 level. Calculations have been carried out in both gas phase and chloroform solution, a polarizable continuum solvation model being used to represent the latter. Results have been compared with those recently obtained for the analogues omega-hydroxy acids, HO-(CH2)n-COOH with n = 3 and 4. The compounds with n = 3 clearly favor coiled conformations, the population expected for extended and semiextended conformations being very low. However, for compounds with n = 4 the minimum energy extended and semiextended structures become considerably more stable. The overall results indicate that the conformational preferences of the central aliphatic segment of omega-methoxy methyl esters and omega-hydroxy acids are not influenced by the formation of intramolecular O-H...O hydrogen bonds.

Journal Article↗
PubMed1993

D-lactate metabolism in patients with chronic renal failure undergoing CAPD.

To clarify the D-lactate metabolism in patients with chronic renal failure undergoing CAPD, plasma levels, loaded doses and urinary excretion of D-lactate were measured. In addition, D-2-hydroxy acid dehydrogenase activities in resected and autopsied specimens were measured. The daily loaded dose of D-lactate by CAPD was 88.9 +/- 1.29 mmol and urinary excretion was negligible. There was no tendency for the plasma D-lactate to accumulate. The enzyme activity was detected in the liver, kidney and pancreas tissues both in the resected and autopsied specimens. The above findings indicate that the loaded D-lactate is catabolized in patients with chronic renal failure undergoing CAPD, and D-2-hydroxy acid dehydrogenase is responsible for the metabolism of D-lactate in humans.

Adolescent↗
PubMed2005

Acyl-coenzyme a formation of simvastatin in mouse liver preparations.

Formation of an acyl-CoA thioester has been proposed, but not directly demonstrated, to be a key step in mediating both lactonization and atypical beta-oxidation of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors. Here, we describe studies to characterize formation of acyl-CoA thioesters in vitro in mouse liver preparations using the hydroxy acid form of simvastatin (SVA) as a model substrate. With an optimized chromatography method, three new products were detected in addition to the dehydration product (P1) and the lactone form of simvastatin, which have been characterized previously (Prueksaritanont et al., 2001). Based on high-pressure liquid chromatography analysis, UV spectroscopy, mass spectrometry, and NMR spectral characterization, two metabolites were identified as acyl-CoA thioester conjugates of SVA and P1, respectively, whereas the third metabolite (M1) was confirmed to be the L-beta-hydroxy isomer of simvastatin. M1 was probably formed by stereospecific hydration, a previously reported reaction, and subsequent lactonization of P1-S-acyl CoA. Among all the mouse liver subcellular fractions, microsomes exhibited the highest capacity to catalyze the CoASH-dependent metabolism of SVA, whereas such activity was totally absent in cytosol. Together, these results provide direct experimental evidence that SVA (and conceivably other statins as well) is able to form an acyl-CoA thioester, possibly by microsomal long-chain acyl-CoA synthetase(s), leading to formation of two parallel metabolic pathways, one resulting in the two diastereomers of statin lactones (simvastatin and M1) and the other to the beta-oxidation pathway of statin hydroxy acids.

Acetyl-CoA C-Acyltransferase↗
PubMed1998

Continuous infusion of low-dose topotecan: pharmacokinetics and pharmacodynamics during a phase II study in patients with small cell lung cancer.

Preclinical schedule dependency suggests that prolonged maintenance of low plasma levels of topotecan, a specific inhibitor of the nuclear enzyme topoisomerase I, results in optimal antitumor activity. The pharmacokinetics and pharmacodynamics of topotecan, administered as single agent in second-line therapy as a continuous low-dose infusion for 21 days, were evaluated in nine patients with small cell lung cancer (SCLC). Topotecan was administered i.v. as a 21 day continuous infusion every 28 days via an ambulatory pump. Dosages ranged from 0.4 to 0.6 mg/m2/day. Plasma levels of topotecan, the sum of topotecan, and its hydroxy acid congener and the N-desmethyl metabolite were determined at 1, 7, 14 and 21 days during infusion, using a validated high-performance liquid chromatography method with fluorescence detection. Myelosuppression was the most important toxicity. All patients experienced anemia, being severe (grade 3/4) in 55% of all courses. Other adverse effects were relatively mild and reversible, and included nausea, vomiting, diarrhea and fatigue. Three patients achieved a partial response. Mean steady-state concentrations of topotecan (C(ss)) in the first course were 0.46+/-0.17 and 0.47+/-0.19 ng/ml after doses of 0.4 and 0.5 mg/m2/day, respectively. Steady-state levels of the total of topotecan and hydroxy acid (C(ss,tot)) were 1.28+/-0.25 (range 0.93-1.58) and 1.57+/-0.19 (range 1.43-1.70) ng/ml at doses of 0.4 and 0.5 mg/m2/day, respectively. The percentage of the administered topotecan dose excreted in the urine within 24 h was 40+/-14 and 1.2+/-1.0% for total topotecan and N-desmethyltopotecan, respectively. During the second course, C(ss,tot) was significantly higher (p=0.032, paired t-test), which suggests altered topotecan disposition. A sigmoidal relationship was found between C(ss,tot) and the percent decrease in platelets (r=0.76, p=0.018). We conclude that topotecan administered as a 21 day continuous low-dose infusion has activity as single-agent, second-line therapy in patients with SCLC. There was considerable interpatient and intrapatient variability in systemic exposure to topotecan. Differences in organ function might contribute to this variation. Serum aspartate aminotransferase and albumin levels were predictive of topotecan pharmacokinetics.

Adult↗
PubMed1989

Bile acid sulfotransferase I from rat liver sulfates bile acids and 3-hydroxy steroids: purification, N-terminal amino acid sequence, and kinetic properties.

A bile acid:3'phosphoadenosine-5'phosphosulfate:sulfotransferase (BAST I) from adult female rat liver cytosol has been purified 157-fold by a two-step isolation procedure. The N-terminal amino acid sequence of the 30,000 subunit has been determined for the first 35 residues. The Vmax of purified BAST I is 18.7 nmol/min per mg protein with N-(3-hydroxy-5 beta-cholanoyl)glycine (glycolithocholic acid) as substrate, comparable to that of the corresponding purified human BAST (Chen, L-J., and I. H. Segel, 1985. Arch. Biochem. Biophys. 241: 371-379). BAST I activity has a broad pH optimum from 5.5-7.5. Although maximum activity occurs with 5 mM MgCl2, Mg2+ is not essential for BAST I activity. The greatest sulfotransferase activity and the highest substrate affinity is observed with bile acids or steroids that have a steroid nucleus containing a 3 beta-hydroxy group and a 5-6 double bond or a trans A-B ring junction. These substrates have normal hyperbolic initial velocity curves with substrate inhibition occurring above 5 microM. Of the saturated 5 beta-bile acids, those with a single 3-hydroxy group are the most active. The addition of a second hydroxy group at the 6- or 7-position eliminates more than 99% of the activity. In contrast, 3 alpha,12 alpha-dihydroxy-5 beta-cholan-24-oic acid (deoxycholic acid) is an excellent substrate. The initial velocity curves for glycolithocholic and deoxycholic acid conjugates are sigmoidal rather than hyperbolic, suggestive of an allosteric effect. Maximum activity is observed at 80 microM for glycolithocholic acid. All substrates, bile acids and steroids, are inhibited by the 5 beta-bile acid, 3-keto-5 beta-cholanoic acid. The data suggest that BAST I is the same protein as hydrosteroid sulfotransferase 2 (Marcus, C. J., et al. 1980. Anal. Biochem. 107: 296-304).

Amino Acid Sequence↗
PubMed1994

Strategic manipulation of the substrate specificity of Saccharomyces cerevisiae flavocytochrome b2.

Flavocytochrome b2 from Saccharomyces cerevisiae acts physiologically as an L-lactate dehydrogenase. Although L-lactate is its primary substrate, the enzyme is also able to utilize a variety of other (S)-2-hydroxy acids. Structural studies and sequence comparisons with several related flavoenzymes have identified the key active-site residues required for catalysis. However, the residues Ala-198 and Leu-230, found in the X-ray-crystal structure to be in contact with the substrate methyl group, are not well conserved. We propose that the interaction between these residues and a prospective substrate molecule has a significant effect on the substrate specificity of the enzyme. In an attempt to modify the specificity in favour of larger substrates, three mutant enzymes have been produced: A198G, L230A and the double mutant A198G/L230A. As a means of quantifying the overall kinetic effect of a mutation, substrate-specificity profiles were produced from steady-state experiments with (S)-2-hydroxy acids of increasing chain length, through which the catalytic efficiency of each mutant enzyme with each substrate could be compared with the corresponding wild-type efficiency. The Ala-198-->Gly mutation had little influence on substrate specificity and caused a general decrease in enzyme efficiency. However, the Leu-230-->Ala mutation caused the selectivity for 2-hydroxyoctanoate over lactate to increase by a factor of 80.

Alanine↗
PubMed1988

Selective induction of peroxisomal enzymes by the hypolipidemic drug bezafibrate. Detection of modulations by automatic image analysis in conjunction with immunoelectron microscopy and immunoblotting.

Quantitative immunoelectron microscopy in conjunction with quantitative analysis of immunoblots have been used to study the effects of bezafibrate (BF), a peroxisome-proliferating hypolipidemic drug, upon six different enzyme proteins in rat liver peroxisomes (Po). Antibodies against following peroxisomal enzymes: catalase, urate oxidase, alpha-hydroxy acid oxidase, acyl-CoA oxidase, bifunctional enzyme (hydratase-dehydrogenase) and thiolase, were raised in rabbits, and their monospecificities were confirmed by immunoblotting. Female Sprague-Dawley rats were treated for 7 days with 250 mg/kg/day bezafibrate and liver sections were incubated with the appropriate antibodies followed by the protein A-gold complex. The labeling density for each enzyme was estimated by automatic image analysis. In parallel experiments immunoblots prepared from highly purified peroxisome fractions of normal and BF-treated rats were incubated with the same antibodies. The antigens were visualized by an improved protein A-gold method including an anti-protein A step and silver amplification. The immunoblots were also quantitated by an image analyzer. The results revealed a selective induction of beta-oxidation enzymes by bezafibrate with thiolase showing the most increase followed by bifunctional protein and acyl-CoA oxidase. The labeling density for catalase and alpha-hydroxy acid oxidase was reduced, confirming fully the quantitative analysis of immunoblots which in addition revealed reduction of uricase. These observations demonstrate that hypolipidemic drugs induce selectively the beta-oxidation enzymes while other peroxisomal enzymes are reduced. The quantitative immunoelectron microscopy with automatic image analysis provides a versatile, highly sensitive and efficient method for rapid detection of modulations of individual proteins in peroxisomes.

Acetyl-CoA C-Acetyltransferase↗
PubMed1994

A pharmacokinetic model of topotecan clearance from plasma and cerebrospinal fluid.

We present a physiological pharmacokinetic model that describes the plasma and cerebrospinal fluid (CSF) concentrations of topotecan [(S)-9-dimethylaminomethyl-10-hydroxyamptothecin hydrochloride, SK&F 104864-A, NSC 609699] following i.v. and intraventricular administrations in monkeys. The model consists of three physical spaces: the CSF, the plasma, and a body compartment. The model incorporates such processes as reversible conversion of topotecan lactone to an inactive hydroxy acid form, microvascular exchange between CSF and plasma, bulk CSF flow, exchange between plasma and body compartments, and elimination of drug from the plasma compartment. Several parameters in the model were obtained from published literature on the physiology of the monkey. The model was then fit to the plasma and CSF data to deduce the other parameters. Calculated clearances of topotecan lactone and total drug from the CSF after intraventricular injection were 3.9 and 2.2 ml/h, respectively. Clearances of topotecan lactone and total drug from the plasma following a 10-min infusion were 26.3 liters/h/m2 and 17.8 liters/h/m2, respectively. The calculated ratios of the area under the concentration curve in the CSF following i.v. infusion to the area under the concentration curve in plasma were 0.11 and 0.19 for topotecan and total drug, respectively, indicating significant CSF penetration. The volume of distribution was 0.77 liters/kg, which represents distribution in a volume approximating total body water. The forward and reverse rate constants for the lactone-to-hydroxy acid conversion were 1.0 and 0.29 h-1, respectively. Comparison of the clearances (normalized to body surface area) with values reported for mice and humans shows reasonable similarity across species. This pharmacokinetic model may help guide future development and refinement of clinical protocols, especially in the treatment of diseases of the central nervous system.

Animals↗
PubMed1991

Estradiol 17 beta-dehydrogenase: full enzymatic activity in the absence of zinc.

The precise catalytic mechanism of the steroid interconverting enzyme, human placental estradiol 17 beta-dehydrogenase (EC 1.1.1.62, estradiol-17 beta:NAD+ 17-oxidoreductase), is not known. Two general models for the catalytic mechanism of dehydrogenases have been defined. One model requires Zn2+ metal for the catalytic event, as has been shown for horse liver alcohol dehydrogenase (EC 1.1.1.1, alcohol:NAD+ oxidoreductase). Another model has been demonstrated for the 2-hydroxy acid dehydrogenases in which histidine residues are necessary for enzyme activity, without participation of a metal ion. In order to define which mechanism might be operative for the placental enzyme, it became important to determine whether Zn2+, or another metal ion, is associated with the macromolecule. Several homogeneous enzyme preparations, having protein concentrations from 5-80 microM, were extensively dialyzed in a buffer containing EDTA. Atomic absorption analysis of each sample demonstrated that no Zn2+ was present, although the enzymatic activity was maintained. In addition, there was no significant detection of Mg2+ or Mn2+ above background levels. When the isolated enzyme was dialyzed against buffer containing added 0.01-20 microM ZnCl2, no increase in specific activity of the enzyme was seen. The data indicate that the presence of zinc is not required for the catalytic event. These results, together with our previous affinity-labeling studies, which demonstrate a histidine residue in the catalytic region of the active site, allow us to propose that the catalytic mechanism of the human placental estradiol 17 beta-dehydrogenase is similar to that of the 2-hydroxy acid dehydrogenases.

Amino Acid Sequence↗
PubMed2003

Two distinct pathways for the formation of hydroxy FA from linoleic acid by lactic acid bacteria.

Twenty-three of 86 strains of lactic acid bacteria transformed linoleic acid into hydroxy FA. Two distinct conversion pathways were in operation. Two strains of Lactobacillus acidophilus and a strain of Pediococcus pentosaceus produced 13(S)-hydroxy-9-octadecenoic acid 113(S)-OH 18:11 and 10,13dihydroxyoctadecanoic acid (10,13-OH 18:0) as main and minor products, respectively, whereas 13 strains, including L. casei subsp. casei, L. paracasei subsp. paracasei, L. rhamnosus, L. lactis subsp. cremoris, and Streptococcus salivarius subsp. thermophilus produced 10-hydroxy-12-octadecenoic acid (10-OH 18:1). Seven strains of L. plantarum converted linoleic acid to 10-hydroxyoctadecanoic acid (10-OH 18:0) through 10-OH 18:1. Linoleic acid at 2 g/L was converted by L. acidophilus IFO13951T to 1.3 g of 13(S)-OH 18:1 and 0.09 g of 10,13-OH 18:0 in 7 d. Lactobacillus paracasei subsp. paracasei JCM 1111 produced 10-OH 18:1 in 91% yield, and L. plantarum JCM 8341, 10-OH 18:0 in 59% yield from linoleic acid (2 g/L) under optimal conditions. To our knowledge, this is the first report on the production of 13(S)-OH 18:1 by lactic acid bacteria other than ruminal bacteria, and of 10,13-OH 18:0 by any bacteria.

Fatty Acids↗
PubMed1987

Metabolism of Monoterpenes : Metabolic Fate of (+)-Camphor in Sage (Salvia officinalis).

The bicyclic monoterpene ketone (+)-camphor undergoes lactonization to 1,2-campholide in mature sage (Salvia officinalis L.) leaves followed by conversion to the beta-d-glucoside-6-O-glucose ester of the corresponding hydroxy acid (1-carboxymethyl-3-hydroxy-2,2,3-trimethyl cyclopentane). Analysis of the disposition of (+)-[G-(3)H]camphor applied to midstem leaves of intact flowering plants allowed the kinetics of synthesis of the bis-glucose derivative and its transport from leaf to root to be determined, and gave strong indication that the transport derivative was subsequently metabolized in the root. Root extracts were shown to possess beta-glucosidase and acyl glucose esterase activities, and studies with (+)-1,2[U-(14)C]campholide as substrate, using excised root segments, revealed that the terpenoid was converted to lipid materials. Localization studies confirmed the radiolabeled lipids to reside in the membranous fractions of root extracts, and analysis of this material indicated the presence of labeled phytosterols and labeled fatty acids (C(14) to C(20)) of acyl lipids. Although it was not possible to detail the metabolic steps between 1,2-campholide and the acyl lipids and phytosterols derived therefrom because of the lack of readily detectable intermediates, it seemed likely that the monoterpene lactone was degraded to acetyl CoA which was reincorporated into root membrane components via standard acyl lipid and isoprenoid biosynthetic pathways. Monoterpene catabolism thus appears to represent a salvage mechanism for recycling mobile carbon from senescing oil glands on the leaves to the roots.

Journal Article↗