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PubMed2000

Synthesis of 2-C-methyl-D-erythritol 4-phosphate: the first pathway-specific intermediate in the methylerythritol phosphate route to isoprenoids.

[reaction: see text] 2-C-methyl-D-erythritol 4-phosphate (4), formed from 1-deoxy-D-xylulose 5-phosphate (3), is the first pathway-specific intermediate in the methylerythritol phosphate route for the biosynthesis of isoprenoid compounds in bacteria, algae, and plant chloroplasts. In this report, 4 was synthesized from 1,2-propanediol (7) in seven steps with an overall yield of 32% and in an enantiomeric excess of 78%.

Erythritol↗
PubMed2001

T cells ignore aniline, a prohapten, but respond to its reactive metabolites generated by phagocytes: possible implications for the pathogenesis of toxic oil syndrome.

The most basic arylamine, aniline, belongs to a class of compounds notorious for inducing allergic and autoimmune reactions. In 1981 in Spain, many people succumbed to toxic oil syndrome (TOS), a disease caused by ingestion of cooking oil contaminated with aniline. Indirect evidence points toward an immune pathogenesis of TOS driven by T lymphocytes, but it is unclear to which antigens these cells could react. Here, using the popliteal lymph node (PLN) assay in mice, we analyzed the sensitizing potential of aniline, its metabolites, and some of the aniline-coupled lipids detected in the contaminated cooking oil. Whereas aniline itself and its non-protein-reactive metabolites nitrobenzene, p-aminophenol and N-acetyl-p-aminophenol, failed to elicit PLN responses, its reactive metabolites nitrosobenzene and N-hydroxylaniline did. The aniline-coupled lipids, namely, linoleic anilide and linolenic anilide, and a mixture of fatty acid esters of 3-(N-phenylamino)-1,2-propanediol, all implicated in TOS, induced significant PLN responses, whereas the respective aniline-free lipids, linoleic acid, linolenic acid, and triolein, did not. Hence, the aniline moiety plays a crucial role in the immunogenicity of the aniline-coupled lipids of TOS. PLN responses to the reactive aniline metabolites and the one aniline-coupled lipid that was tested, linolenic anilide, were T-cell-dependent. Secondary PLN responses to nitrosobenzene were detectable not only after priming with nitrosobenzene but, in some experiments, also after priming with linolenic anilide. This suggests that the aniline moiety was cleaved from the aniline-coupled lipid and metabolized to the intermediate nitrosobenzene that generated the prospective neoantigens. Consistent with this, in lymphocyte proliferation tests in vitro, T cells primed to nitrosobenzene reacted in anamnestic fashion to white bone marrow cells (WBMCs) pulsed with aniline. Hence, we propose that aniline is a prohapten that can be metabolized by WBMCs, which form neoantigens that are recognized by T cells. The possible significance of these findings for the pathogenesis of TOS is discussed.

Aniline Compounds↗
PubMedDate not supplied

Conversion of a hemoglobin alpha chain aspartate(47) ester to N-(2,3-dihydroxypropyl)asparagine as a method for identification of the principal binding site for benzo[a]pyrene anti-diol epoxide.

Human hemoglobin was alkylated with (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) and then treated with aqueous (+/-)-3-amino-1,2-propanediol to convert alkylated carboxyl side chains to N-(2,3-dihydroxypropyl) amides. Tryptic peptides produced from the modified protein were subjected to affinity chromatography on phenylboronic acid. The bound fraction was further purified by HPLC on C-4 reverse-phase medium to yield one modified peptide, which was identified as the Thr(41)-Lys(56) peptide of the alpha chain by amino acid analysis, Edman sequencing analysis, and FAB-MS. Limited direct evidence from this study and further indirect evidence from previous work identify Asp(47) alpha as the amino acid reacting with BPDE. The only other likely sites would be the C-terminal carboxyl groups of either the alpha or beta chain. Possible reasons for the site selectivity of the alkylation of human hemoglobin by BPDE are discussed.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1995

Identification of N-acetylcysteine conjugates of 1,2-dibromo-3-chloropropane: evidence for cytochrome P450 and glutathione mediated bioactivation pathways.

The haloalkane 1,2-dibromo-3-chloropropane (DBCP) is a carcinogen, mutagen, nephrotoxin, and testicular toxin. The identification of N-acetylcysteine conjugates of DBCP provides information on GSH mediated and cytochrome P450 mediated bioactivation pathways in the expression of DBCP-induced toxicities. N-Acetylcysteine conjugates excreted in the urine of male Sprague-Dawley rats administered DBCP, C1D2-DBCP, C2D1-DBCP, C3D2-DBCP, or D5-DBCP (80 mg/kg) were purified by reverse-phase HPLC as their methyl ester derivatives and characterized by fast atom bombardment tandem mass spectrometry. These metabolites were also converted to tert-butyldimethylsilyl ether derivatives and analyzed by gas chromatography-mass spectrometry (GC-MS) to facilitate the identification of N-acetyl-S-(2,3-dihydroxypropyl)cysteine (Ia), an apparent regioisomer of Ia, 2-(S-(N-acetylcysteinyl))-1,3-propanediol (Ib), N-acetyl-S-(3-hydroxypropyl)cysteine (IIa), and N-acetyl-S-(3-chloro-2-hydroxypropyl)-cysteine (III). Metabolites Ia, Ib, and III displayed quantitative retention of deuterium, an observation consistent with the formation of episulfonium ion intermediate(s) in their biogenesis. Mercapturate IIa retained three atoms of deuterium from D5-DBCP, and two atoms of deuterium from the dideuterio analogs (C1D2-DBCP and C3D2-DBCP), thus invoking P450 mediated formation of 2-bromoacrolein (2-BA) as an intermediate in the biogenesis of IIa. A mechanism is proposed in which conjugate addition of GSH to 2-BA, subsequent episulfonium ion formation, and addition of GSH afford 1,2-(diglutathion-S-yl)propanal. Glutathione mediated reduction is invoked to afford S-(3-hydroxypropyl)GSH which would be excreted in the urine as IIa. The quantitative retention of deuterium from C1D2-DBCP or C3D2-DBCP was indicative of isotopically sensitive branching of P450 metabolism at either C1 or C3 to afford 2-BA. C2D1-DBCP showed a 30% retention of 1 deuterium atom in IIa; the loss of the deuterium is consistent with 2-BA formation, whereas the retention of one deuterium atom is indicative of the formation of metabolite IIa through GSH conjugation of either 2,3-dibromopropanal or 2-bromo-3-chloropropanal. These data indicate that IIa is a marker metabolite for the potent direct-acting mutagen, 2-BA, or its metabolic precursors 2,3-dibromopropanal or 2-bromo-3-chloropropanal. Therefore, evidence has been presented for bioactivation of DBCP by glutathione and cytochrome P450 mediated mechanisms.

Acetylcysteine↗
PubMed2004

Investigating the role of 2-phenylpropenal in felbamate-induced idiosyncratic drug reactions.

Felbamate (2-phenyl-1,3-propanediol dicarbamate, FBM) can cause aplastic anemia and hepatotoxicity. The mechanism of FBM-induced toxicities is unknown; however, it has been proposed that 2-phenylpropenal, a reactive metabolite of FBM, is responsible. The pathway leading to this metabolite involves hydrolysis of FBM to 2-phenyl-1,3-propandiol monocarbamate (MCF), oxidation to 3-carbamoyl-2-phenylpropionaldehyde (CBMA), and spontaneous loss of carbon dioxide and ammonia. We made a polyclonal antibody against 2-phenylpropenal bound to protein and confirmed its specificity using ELISA. We attempted to develop an animal model of FBM-induced aplastic anemia and/or hepatotoxicity, and we also used the antibody to try to detect covalent binding of 2-phenylpropenal using immunoblotting. However, none of the animals developed evidence of bone marrow or liver toxicity, and we were unable to detect covalent binding, possibly because significantly less 2-phenylpropenal is formed in rodents than in humans. As this type of idiosyncratic drug reaction is believed to be immune-mediated, we also studied the potential of FBM and its metabolites to stimulate an immune response using the reporter antigen popliteal lymph node assay in female Balb/c mice. We found that neither FBM nor MCF induced an immune response in popliteal lymph nodes (PLNs). However, CBMA treatment appeared immunogenic, causing footpad inflammation, hardening, scab formation, and an increase in thickness. The PLN cell count in CBMA-treated mice increased 8-fold as compared to control, FBM-, or MCF-treated mice. Immunohistochemical analysis of the CBMA-exposed PLNs revealed germinal center formation, indicating B cell proliferation, later confirmed by flow cytometry. Most of the cells expressing the activation surface marker CD54 were B cells. We also found that CBMA treatment caused an increase in the production of IgM and IgG1 antibodies as well as IL-4 and IFN-gamma cytokines. Our findings indicate that 2-phenylpropenal is a very potent immunogen, supporting its possible involvement in the FBM-induced hepatotoxicity and aplastic anemia.

Aldehydes↗
PubMed2004

Studies on toxic oil syndrome: stereoselective hydrolysis of 3-(phenylamino)propane-1,2-diol esters by human pancreatic lipase.

The ingestion of rapeseed oil batches denatured with aniline and illegally refined and distributed by street vendors was responsible for toxic oil syndrome (TOS), an intoxication episode that took place in Spain in 1981, causing over 400 deaths and affecting more than 20,000 people. Despite the intense research efforts carried out to date, the compounds responsible for that intoxication have not been elucidated. Nevertheless, epidemiological studies have pointed to fatty acid mono- and diesters of 3-phenylamino-1,2-propanediol (PAP) as the biomarkers of those toxic oil batches. The structure of these esters bears common features with that of triglycerides, which suggested that PAP esters could follow the route of lipids metabolism up to a certain extent. The incubation of racemic PAP dioleyl ester with human pancreatic lipase (hPL) led to the formation of the corresponding stereoisomeric monoesters bearing the oleyl residue at C-2, although a kinetic resolution in favor of the (S)-enantiomer was observed. These monoesters are unstable and in equilibrium with their corresponding regioisomers with the acyl residue at C-1, apparently without the intervention of the lipase. Finally, incubations of these latter monoesters with hPL led to the formation of the respective PAP enantiomers. Again, the kinetic resolution of this hydrolytic process favored the formation of the enantiomer with the (S)-configuration. Taken together, these results showed that PAP esters are substrates of hPL and that the two hydrolytic steps exhibit kinetic resolution in favor of the (S)-enantiomers.

Brassica rapa↗
PubMed1996

Products of aniline and triglycerides in oil samples associated with the toxic oil syndrome.

The toxic oil syndrome (TOS) was a devastating disease that occurred in Spain in 1981. The disease was associated with the consumption of aniline-denatured and refined rapeseed oil that had been illegally sold as olive oil. Many aniline-derived oil components have been identified in the oils; however, no etiological agent has ever been identified for this disease. We have continued the study of the TOS problem by applying new technology in the form of liquid chromatography interfaced via atmospheric pressure ionization with tandem mass spectrometry. Using liquid chromatography tandem mass spectrometry, we studied diluted TOS-associated oils by direct analysis without prior sample treatment. Using this technology, we found new classes of compounds that are associated with disease-related oils. The compounds that have been identified are esters and ester amides of 3-(N-phenylamino)-1,2-propanediol and are products of aniline and triglycerides. Because of the varied fatty acid (oleic acid, etc.) content of the oils, many variations of the above compounds are possible. We now report the identities of more than 20 compounds not previously identified. These compounds are strongly associated with oils that caused the toxic oil syndrome. We believe these compounds should be considered for future animal studies.

Anilides↗
PubMed1996

Synthesis and in vitro reactivity of 3-carbamoyl-2-phenylpropionaldehyde and 2-phenylpropenal: putative reactive metabolites of felbamate.

We propose that 3-carbamoyl-2-phenylpropionaldehyde is an intermediate in the metabolism of felbamate, an anti-epileptic drug with a unique profile of the therapeutic activity, and undergoes a cascade of chemical reactions responsible for the toxic properties of the parent drug. To test this hypothesis, we have synthesized 3-carbamoyl-2-phenylpropionaldehyde and evaluated its in vitro reactivity. This molecule was found to be highly unstable at physiological pH (t1/2 < or = 30 s) and to undergo facile elimination to 2-phenylpropenal, an alpha, beta-unsaturated aldehyde commonly termed atropaldehyde. However, the predominant reaction pathway for 3-carbamoyl-2-phenylpropionaldehyde was reversible cyclization to generate 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one, a urethane that has a considerably longer half-life at physiological pH (t1/2 > or = 5 h) and may serve as a stable reservoir of the reactive aldehyde both in vitro and in vivo. Atropaldehyde is a potent electrophile and was found to exhibit cytotoxicity to cultured fibroblasts (50% growth inhibition (GI50) = 4.1 +/- 1.1 microM) comparable to the known unsaturated aldehyde toxins, 4-hydroxy-2-nonenal and acrolein. 3-Carbamoyl-2-phenylpropionaldehyde also exhibited significant cytotoxicity (GI50 = 53 +/- 8 microM), whereas 2-phenyl-1,3-propanediol monocarbamate (GI50 > 500 microM) and 3-carbamoyl-2-phenylpropionic acid (GI50 > 500 microM) were nontoxic. We have additionally demonstrated the formation of a glutathione-atropaldehyde conjugate from the in vitro incubation of 3-carbamoyl-2-phenylpropionaldehyde with glutathione. Thus, the potent cytotoxicity and potential allergenicity of atropaldehyde implicate this unsaturated aldehyde as a possible causative agent in the toxicities observed with felbamate treatment.

Aldehydes↗
PubMed1999

13C(2)-Labeled methyl tert-butyl ether: toxicokinetics and characterization of urinary metabolites in humans.

After exposure to methyl tert-butyl ether (MTBE), a gasoline additive, only one metabolite [tert-butyl alcohol (TBA), <1% of dose] has been identified in human urine [Nihlén, A., et al. (1998) Toxicol. Appl. Pharmacol. 148, 274-280]. In the study presented here, metabolites of MTBE were characterized by (1)H-decoupled (13)C NMR spectroscopy in urine obtained from four volunteers experimentally exposed to 50 ppm (13)C-labeled MTBE ([1,2-(13)C(2)]MTBE) vapor (facemask) for 2 h during a light physical work load (50 W). Chemical shifts for the two adjacent (13)C-labeled carbons in [1, 2-(13)C(2)]MTBE-derived metabolites were consistent with the shifts obtained for spiked standards of alpha-hydroxyisobutyric acid (HBA) and 2-methyl-1,2-propanediol (MPD). NMR signals were not detected for labeled MTBE, TBA, or possible MTBE-derived conjugates. Quantification of HBA and MPD was performed by NMR for two urine samples (collected 20 h after exposure). One subject had 11% HBA and 1% MPD, and the other individual had 3% HBA and 1% MPD in the urine, expressed as a percentage of MTBE uptake. This indicates that HBA and MPD occur at significantly higher levels in the urine (detected by NMR) than MTBE and TBA (detected by GC). To our knowledge, this is the first characterization of MTBE metabolites, other than TBA, in humans. Further urine, blood, and expired air were collected up to 22 h after exposure, and the toxicokinetics of MTBE, TBA, and acetone were determined by GC. Low relative uptake (39%), a low level of postexposure exhalation of MTBE (17%), and low recovery of TBA in the urine (<1%) were observed. The same subjects had previously been exposed to unlabeled MTBE in a whole-body exposure study [Nihlén, A., et al. (1998) Toxicol. Appl. Pharmacol. 148, 274-280], and the toxicokinetics of MTBE and TBA in this facemask exposure did not differ from the previous whole-body chamber exposure.

Adult↗
PubMed2001

Comparison of the cryopreservation of human embryos obtained after intracytoplasmic sperm injection with a slow cooling or an ultrarapid cooling procedure.

PURPOSE: Our purpose was to compare an ultrarapid method (URM) modified with dimethyl sulfoxide (Me2SO) to a slow method (SM) with propanediol (PROH) for the cryopreservation of extra human embryos in a program of intracytoplasmic sperm injection (ICSI). METHODS: The extra embryos of 160 patients were cryopreserved in a prospective and randomized manner (drawing lots) by a modified URM (3 M Me2SO/0.25 M sucrose/thawing in three sucrose gradients) (Group I) or by a SM (1.5 M Propanediol/program 0-Cryologic CL863) (Group II). A total of 103 cycles has been thawed thus far. The number of thawed cycles was 58 for group I and 45 for group II. RESULTS: The mean age (group I, 31.3 +/- 4.5; group II, 31.9 +/- 4.3) did not differ between the groups (P = 0.38). The number of frozen embryos (group I, 6.6 +/- 3.2; group II, 6.5 +/- 3.2) was similar (P = 0.49) for the two groups, as was the number of thawed embryos (P = 0.52) (group I, 6.5 +/- 2.9; group II, 6.2 +/- 3). The survival rate was higher (P < 0.01) for group II (83.3 +/- 23%) than for group I (69.2 +/- 28.7%). The cleavage rate was also higher (P < 0.01) for group II (56.8 +/- 31%) compared with group I (24.2 +/- 22.4%). The number of embryos transferred did not differ (P = 0.14) between the groups (group I, 3.16 +/- 1.2; group II, 3.5 +/- 1.0). The implantation rate (group I, 6.3%; group II, 13.8%) was significantly different between groups (P = 0.034). Pregnancy rates per thawed and transferred cycle were higher for group II (33.3 and 36.6%, respectively) compared with group I (13.8 and 16%, respectively), and these differences were significant (P = 0.03 and P = 0.03, respectively). CONCLUSION: The data obtained suggest that the SM is superior to the URM for the cryopreservation of extra embryos after ICSI.

Adult↗
PubMed1999

The outcome of cryopreserved human embryos after intracytoplasmic sperm injection and traditional IVF.

OBJECTIVE: Our objective was to analyze the outcome of cryopreserved embryos obtained after intracytoplasmic sperm injection (ICSI) and in vitro fertilization (IVF) in terms of survival rate, implantation rate (IR), total and clinical pregnancy rate (PR) in a retrospective, comparative study. METHODS: Three hundred seventy-five IVF and 463 ICSI surnumerary cleaved embryos, frozen on Day 2 with 1,2-propanediol, were thawed. RESULTS: Thirty-two percent of the thawed IVF embryos survived and 11 pregnancies (8 clinical) were obtained from 68 transfers (16.1%). Fourty-seven percent of the ICSI embryos survived, with 19 pregnancies (18 clinical) from 116 transfers (16.4%). The IR was 8.5% (8/94) in IVF cycles and 10.8% (20/185) in ICSI cycles. CONCLUSIONS: A significantly better survival rate of ICSI embryos was observed but with no difference in PR, preclinical, and clinical abortion rate, or IR.

Adult↗
PubMed1999

Comparison of pregnancy outcome of pronuclear- and multicellular-stage frozen-thawed embryo transfers.

PURPOSE: Our purpose was to determine if supernumerary embryos generated by in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) should be frozen (using 1,2-propanediol) at the pronuclear or multicellular stage. METHODS: The study was a retrospective analysis conducted at the Dubai Gynaecology & Fertility Centre of the Department of Health & Medical Services, Dubai, U.A.E. One hundred forty-one women undergoing frozen-thawed embryo replacement cycles with IVF generated embryos and 84 women undergoing the same with ICSI generated embryos. RESULTS: Supernumerary, IVF-generated embryos frozen at the multicellular stage had a significantly higher rate of survival on thawing (73.9%) than embryos frozen at the pronuclear stage (64.4%). The morphological grades of the embryos in the two groups were similar, but a significantly higher pregnancy rate was obtained with embryos frozen at the multicellular stage (22.8%) than with pronuclear-stage embryos (14.8%). Similarly, with ICSI-generated embryos, significantly higher survival was seen with multicellular-stage frozen embryos (74.8%) than pronuclear-stage embryos (64.4%). The morphological grades of the embryos and pregnancy outcomes of the two groups were similar. CONCLUSIONS: Supernumerary embryos generated by IVF and ICSI should be frozen at the multicellular stage so as to allow selection of the best embryos for transfer and embryo freezing of only robust embryos.

Blastocyst↗
PubMed1999

Fertilization, embryo quality, and cryosurvival in in vitro fertilization and intracytoplasmic sperm injection cycles.

PURPOSE: Our purpose was to investigate the influence of semen quality on fertilization, embryo morphology, cleavage, and cryosurvival in conventional in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) programs. METHODS: A retrospective analysis of 513 couples undergoing IVF and 255 couples undergoing ICSI was done. RESULTS: Semen quality influenced fertilization in IVF and abnormal fertilization in IVF and ICSI, but no effects on the development, morphology, implantation capacity, or cryosurvival of embryos were found. Fertilization, embryo quality, and cryosurvival rates were similar after IVF and ICSI. The fertilization rate of mature oocytes in IVF was lower when cytoplasmic immaturity in the oocyte population was frequent. The speed of development of embryos was 2 hr faster after ICSI than after IVF. Two-cell-stage embryos survived best after cryopreservation with propanediol and sucrose on day 2. CONCLUSIONS: After fertilization, semen parameters had no effect on the quality or cryosurvival of embryos in either IVF or ICSI.

Adult↗
PubMed2003

Induction of suppressed ADH activity in Drosophila pachea exposed to different alcohols.

Laboratory-reared males of the cactophilic Drosophila pachea exhibit a spontaneous and sex-specific suppression of alcohol dehydrogenase (ADH) activity within 4 days after eclosion. A lack of ADH activity also is usually seen in wild-caught males, although relatively high activity is always seen in female flies. In the present study we examined the effectiveness of different alcohols and related compounds, including several found naturally in necroses of the host cactus, to induce suppressed ADH activity in wild males of D. pachea and to serve as enzyme substrates. The primary alcohols (methanol, ethanol, 1-propanol, 1-butanol, and 1-pentanol), and the secondary alcohols (2-propanol and 2-butanol), each induced activity after 24 h exposure, although to different degrees. 1,2-Propanediol was usually effective as an inducer, but 2,3-butanediol usually was ineffective. Little or no induction was seen with 1-octanol, 2-pentanol, 3-methyl-1-butanol, 3-hydroxy-2-butanone, or acetaldehyde. Although the compounds tested varied in their ability to function as ADH substrates, methanol was the only alcohol that showed no activity staining. Ethanol induction of ADH activity was apparent after 3-6 h exposure and induced activity decreased dramatically within 1 week of flies being placed in an alcohol-free environment. Ethanol exposure did not induce ADH in adult female D. pachea, or in adult males and females of D. acutilabella in which control males show reduced ADH activity compared to females. The implications of the loss of ADH activity in adult males of D. pachea, as they relate to feeding ecology and fitness, are discussed.

Alcohol Dehydrogenase↗
PubMed2003

Determination of the dermal penetration of esterom components using microdialysis sampling.

PURPOSE: Esterom Solution, an investigational pharmaceutical product, is derived from the esterification of benzoylmethylecgonine (cocaine) in 1.2 propanediol. The resulting solution contains a mixture of components. Esterom Solution is intended to be a topical analgesic to relieve pain and increase the range of motion in patients suffering from acute inflammation of the shoulder or back. Although the components of Esterom are known, the components that are responsible for analgesia have only recently been identified. The purpose of this research is to evaluate which components have the ability to penetrate the skin, how much actually penetrates, and if and/or how each component is metabolized and distributed locally. METHODS: Linear microdialysis probes were implanted into rat dermis. The individual components present in the Esterom Solution were applied separately to the dermis directly over a probe. Dermal dialysis samples were collected to evaluate the dermal penetration of each compound following topical application. RESULTS: Following a 10 mg/50 microL application. 1.8 +/- 0.6 mM benzoic acid was detected at the plateau after approximately 220 min. Following hydroxypropyl benzoic acid application, complete hydrolysis to benzoic acid was observed with a plateau concentration of 137 +/- 19 microM (150 min plateau). When applied separately, hydroxypropyl benzoylecgonine and ecgonine penetrate the skin with plateau concentrations of 32 +/- 9 microM (15 h plateau) and 36 +/- 5 microM (150 min plateau) respectively. Benzoylecgonine, the hydrolytic product of HP-BE, was also detected with a plateau concentration of 3.9 +/- 0.1 microM (16 h plateau) Applied topically, ecgonidine, methylecgonidine, benzoylecgonine, and hydroxypropyl ecgonidine were not detected. CONCLUSIONS: Of the components with analgesic activity, the only compound that penetrates the skin is hydroxypropyl benzoylecgonine. Dermal microdialysis was shown to be an effective technique to monitor the skin penetration of topically applied compounds.

Administration, Topical↗
PubMed2000

Glucocorticoid receptor antagonist RU 486 treatment reduces periodontitis in Fischer 344 rats.

Inappropriate hypothalamic pituitary adrenal (HPA) axis regulation of immune responses to bacterial challenges has been found to play an important role in infections and inflammatory disease susceptibility and progression. In the present study we investigated the tissue effects of experimental periodontitis in Fischer 344 rats, which were subcutaneously (s.c.) injected with 20 mg/kg of the glucocorticoid receptor antagonist and active antiglucocorticoid agent RU 486 every second day over a period of 14 d. Periodontitis was induced by placing a bacterial plaque retentive silk ligature in the gingival sulcus around the neck of maxillary right 2nd molar teeth 1 d after the first injection in 10 RU 486-treated and 10 vehicle (1,2-propanediol)-treated control animals. The contralateral maxillary left 2nd molars served as internal control teeth for naturally occurring periodontitis. Disease progression was evaluated radiographically and histometrically. The average level of corticosterone in blood at sacrifice was significantly lower in the RU 486-treated animals as compared to controls. The experimental animals also developed significantly less periodontal breakdown at both experimental and control teeth compared to the vehicle-treated control animals. The results support our recent findings showing that HPA hyper-reactivity, either genetically determined or experimentally induced, stimulates periodontal disease susceptibility. These findings suggest that central nervous regulation of inflammatory responses to dental plaque microorganisms in the gums may modulate periodontal disease susceptibility and progression.

Animals↗
PubMed1999

Action of BTN1, the yeast orthologue of the gene mutated in Batten disease.

Neuronal ceroid-lipofuscinoses (NCL) are autosomal recessive disorders that form the most common group of progressive neurodegenerative diseases in children, with an incidence as high as 1 in 12,500 live births, and with approximately 440,000 carriers in the United States. Disease progression is characterized by a decline in mental abilities, increased severity of untreatable seizures, blindness, loss of motor skills and premature death. The CLN3 gene, which is responsible for Batten disease, has been positionally cloned. The yeast gene, denoted BTN1, encodes a non-essential protein that is 39% identical and 59% similar to human CLN3. Strains lacking Btn1p, btn1-delta, are resistant to D-(-)-threo-2-amino-1-[p-nitrophenyl]-1,3-propanediol (ANP) in a pH-dependent manner. This phenotype was complemented by expression of human CLN3, demonstrating that yeast Btn1p and human CLN3 share the same function. Here, we report that btn1-delta yeast strains have an abnormally acidic vacuolar pH in the early phases of growth. Furthermore, DNA microarray analysis of BTN1 and btn1-delta strains revealed differential expression of two genes, with at least one, HSP30, involved in pH control. Because Btn1p is located in the vacuole, we suggest that Batten disease is caused by a defect in vacuolar (lysosomal) pH control. Our findings draw parallels between fundamental biological processes in yeast and previously observed characteristics of neurodegeneration in humans.

Cell Division↗
PubMed2002

Yarrowia lipolytica as a potential producer of citric acid from raw glycerol.

AIMS: To study the biochemical response of Yarrowia lipolytica LGAM S(7)1 during growth on raw glycerol (the main by-product of bio-diesel production units) in order to produce metabolic products of industrial significance. METHODS AND RESULTS: Yarrowia lipolytica was cultivated on raw glycerol or glucose in flasks. Although nitrogen-limited media were employed, growth was not followed by production of reserve lipid. Nitrogen limitation led to citric acid excretion. Growth and citric acid production parameters on glycerol were similar to those obtained on glucose. When high initial glycerol media were used, citric acid up to 35 g l(-1) (yield 0.42-0.44 g acid g(-1) glycerol consumed) was produced. CONCLUSIONS: Raw glycerol was an adequate substrate for Y. lipolytica. Growth was not followed by reserve lipid accumulation, but amounts of citric acid were produced. SIGNIFICANCE AND IMPACT OF THE STUDY: Raw glycerol is an industrial feedstock appearing in increasing quantities as the main by-product of bio-diesel production facilities. The present study describes an alternative way of glycerol valorization, with the production of remarkable amounts of citric acid, in addition to its main valorization way (production of 1,3-propanediol by bacteria).

Biomass↗