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PubMed2001

Chirality inversion in the bilirubin molecular exciton.

The bichromophoric pigment bilirubin acts as a molecular exciton in its UV-visible and circular dichroism (CD) spectroscopy. In both polar and nonpolar solvents, an optically active analog, (beta R,beta 'R)-dimethylmesobilirubin-XIII alpha (1), exhibits intense bisignate CD Cotton effects in the region of its long wavelength UV-vis absorption near 400 nm: Delta epsilon(434)(max) + 337, Delta epsilon(389)(max) - 186 (CHCl(3)), and Delta epsilon(431)(max) + 285, Delta epsilon(386)(max) - 177 (CH(3)OH). However, introduction of an amine into a CHCl(3) solution of 1 causes the Cotton effect signs to become inverted, e.g., after addition of NH(3), Delta epsilon(433)(max) - 345, Delta epsilon(389)(max) + 243, and after addition of ethylene diamine, Delta epsilon(435)(max) - 420, Delta epsilon(390)(max) + 299. The sign inversions imply inversion of molecular chirality of the bilirubin and the phenomenon appears to be general for amines, including alpha,omega-diamines. 1,8-Diaminooctane was found to be more effective than longer or shorter chain analogs in producing CD sign inversion.

Bilirubin↗

PubMed2006

Chiral inversion of RS-8359: a selective and reversible MAO-A inhibitor via oxido-reduction of keto-alcohol.

RS-8359, (+/-)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]-pyrimidine is a selective and reversible MAO-A inhibitor. The (S)-enantiomer of RS-8359 has been demonstrated to be inverted to the (R)-enantiomer after oral administration to rats. In the current study, we investigated the chiral inversion mechanism and the properties of involved enzymes using rat liver subcellular fractions. The 7-hydroxy function of RS-8359 was oxidized at least by the two different enzymes. The cytosolic enzyme oxidized enantiospecifically the (S)-enantiomer with NADP as a cofactor. On the other hand, the microsomal enzyme catalyzed more preferentially the oxidation of the (S)-enantiomer than the (R)-enantiomer with NAD as a cofactor. With to product enantioselectivity of reduction of the 7-keto derivative, it was found that only the alcohol bearing (R)-configuration was formed by the cytosolic enzyme with NADPH and the microsomal enzyme with NADH at almost equal rate. The reduction rate was much larger than the oxidation rate of 7-hydroxy group. The results suggest that the chiral inversion might occur via an enantioselectivity of consecutive two opposing reactions, oxidation and reduction of keto-alcohol group. In this case, the direction of chiral inversion from the (S)-enantiomer to the (R)-enantiomer is governed by the enantiospecific reduction of intermediate 7-keto group to the alcohol with (R)-configuration. The enzyme responsible for the enantiospecific reduction of the 7-keto group was purified from rat liver cytosolic fractions and identified as 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) via database search of peptide mass data obtained by nano-LC/MS/MS.

3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)↗

PubMed1990

Metabolic chiral inversion of ibuprofen in isolated rat hepatocytes.

Ibuprofen was used to demonstrate that isolated rat hepatocytes offer a suitable in vitro model to investigate the metabolic chiral inversion of anti-inflammatory 2-arylpropionic acids (profens). The inversion of the pharmacologically inactive (-)-(R)-ibuprofen to the active (+)-(S)-ibuprofen was shown to obey apparent first-order kinetics during 5 h and to increase linearly with increasing hepatocyte concentration up to 4 x 10(5) cells/ml. No elimination of (R)-ibuprofen by routes other than inversion was seen, whereas the elimination of (S)-ibuprofen appeared to be saturable.

Animals↗

PubMed1992

Pulmonary inversion of 2-arylpropionic acids: influence of protein binding.

The possible contribution of pulmonary metabolism to the putative first-pass metabolism of 2-arylpropionic acid nonsteroidal antiinflammatory drugs has not been documented. Isolated perfused rabbit lungs, perfused with 4.5% bovine serum albumin or 5% dextran, were used to study the pulmonary elimination of (R)- and rac-ibuprofen, fenoprofen, and flurbiprofen. In the absence of protein binding, ibuprofen was metabolized via inversion and other pathways, whereas fenoprofen metabolism was essentially restricted to inversion of the (R)-enantiomer; fraction inverted (+/- SE) was 0.37 +/- 0.05 for (R)-ibuprofen and 0.85 +/- 0.03 for (R)-fenoprofen. In the presence of protein, neither ibuprofen nor fenoprofen was metabolized. Flurbiprofen did not undergo pulmonary elimination under any condition studied. This study illustrates that even though a tissue is capable of metabolism, particularly inversion of 2-arylpropionics, the quantitative importance of such elimination pathways may be minimal in the presence of the high degree of protein binding that is characteristic of these drugs.

Animals↗

PubMed1993

Microbial metabolism of 2-arylpropionic acids: chiral inversion of ibuprofen and 2-phenylpropionic acid.

The metabolism of (R,S)-ibuprofen has been investigated in 24 microbial cultures. Of these Cunninghamella elegans, Mucor hiemalis, and Verticillium lecanii catalyzed the oxidation of the drug to 2-[4-(2-hydroxy-2-methylpropyl)phenyl]propionic acid, a known mammalian metabolite. The extent of metabolism was greatest with V. lecanii, with some 47% of the substrate being consumed over a 7-day incubation period. Enantiomeric analysis indicated stereoselective metabolism of (R)-ibuprofen, the enantiomeric composition of the residual substrate being R/S = 0.25. Following a preparative scale incubation of (R,S)-ibuprofen with V. lecanii, in which the reaction was allowed to go to completion, the metabolite was found to be predominantly of the S-configuration (S/R = 2.1), suggesting that chiral inversion of either the drug and/or the metabolite had taken place. Analysis of extracts following incubation of (R,S)-, (R)-, and (S)-2-phenylpropionic acid with V. lecanii, for 21 days, indicated that chiral inversion of the (R)-enantiomer to its optical antipode had taken place. The results of these investigations indicate that microorganisms, in addition to mammals, are able to mediate the chiral inversion of 2-arylpropionic acids. This observation may have implications for the preparation of optically pure 2-arylpropionic acids.

Ibuprofen↗

PubMed1999

Global T-wave inversion: limited QT dispersion despite QTc prolongation--a correlate of benignity in patients with strikingly abnormal electrocardiograms.

BACKGROUND: The global T-inversion (GTI) electrocardiogram (ECG) is strikingly abnormal with major QTc prolongation, but with a surprisingly good prognosis by Kaplan-Meier curve. This contrasts with most significant QTc prolongations. HYPOTHESIS: This study was undertaken to ascertain QT interval dispersion (QTd) in global T wave inversion, a clinically benign long QTc ECG. METHODS: Longest and shortest QT intervals in all 12 leads in 35 consecutive patients with GTI were determined by two mutually blinded observers. QTd was determined by subtraction (maximum-minimum) and QTc was calculated using the Bazett formula. RESULTS: There was a 2:1 female preponderance QTc was prolonged and equal for men (0.471) and women (0.469). Observer variability of under 2% permitted averaging of QT measurements. Composite mean QTd was 55 ms. The literature revealed a range of QTd in normal subjects of 39 to 59 ms (mostly 49 to 59 ms). Patient series with abnormal QTd were well above this level. CONCLUSION: Despite a strikingly abnormal ECG with marked QTc prolongation, QT dispersion was limited in global T inversion, consistent with its previously demonstrated benignity.

Arrhythmias, Cardiac↗

PubMed2002

Use of inverse PCR to amplify and sequence breakpoints of HPRT deletion and translocation mutations.

Deletion and translocation mutations have been shown to play a significant role in the genesis of many cancers. The hprt gene located at Xq26 is a frequently used marker gene in human mutational studies. In an attempt to better understand potential mutational mechanisms involved in deletions and translocations, inverse PCR (IPCR) methods to amplify and sequence the breakpoints of hprt mutants classified as translocations and large deletions were developed. IPCR involves the digestion of DNA with a restriction enzyme, circularization of the fragments produced, and PCR amplification around the circle with primers oriented in a direction opposite to that of conventional PCR. The use of this technique allows amplification into an unknown region, in this case through the hprt breakpoint into the unknown joined sequence. Through the use of this procedure, two translocation, one inversion, and two external deletion hprt breakpoint sequences were isolated and sequenced. The isolated IPCR products range in size from 0.4 to 1.8 kb, and were amplified from circles ranging in size from 0.6 to 7.7 kb. We have shown that inverse PCR is useful to sequence translocation and large deletion mutant breakpoints in the hprt gene.

Base Sequence↗

PubMedDate not supplied

Inversion of Zenker's diverticulum: the preferred option.

A review of patients who had surgery for Zenker's diverticulum in our institution in recent years was conducted. A comparison of inversion versus excision of the sac shows that inversion carries lower morbidity and more rapid rehabilitation of swallowing than does excision. Inversion (plus cricopharyngeal myotomy) is to be preferred for diverticula that are neither too large to invert nor too longstanding to risk leaving subclinical carcinoma behind in the wall of the diverticulum.

Adult↗

PubMed2006

RASSF1A hypermethylation and its inverse correlation with BRAF and/or KRAS mutations in MSI-associated endometrial carcinoma.

Both hypermethylation of the tumor suppressor gene RASSF1A and activating mutations of the KRAS and/or BRAF gene have been reported in a variety of human cancers. To investigate these epigenetic and genetic alterations in endometrial carcinoma (EC), we examined their frequency in 4 uterine EC cell lines and in 75 sporadic primary ECs. Using methylation specific PCR, we found RASSF1A methylation in 25 of 75 (33.3%) ECs. RASSF1A methylation was significantly associated with microsatellite instability (MSI, p < 0.001) and also with hMLH1 methylation (p < 0.001). KRAS mutations were detected in 14 of 75 (18.7%) ECs. BRAF mutations were identified in only 3 of 75 (4.0%) ECs and were not found in ECs with KRAS mutations or RASSF1A methylation. RASSF1A methylation was more frequent in KRAS mutation-negative ECs than in KRAS mutation-positive ECs (37.7% vs 14.3%), but this inverse correlation is not statistically significant (p = 0.122). However, we observed that RASSF1A methylation was inversely correlated with KRAS and/or BRAF mutations (p = 0.028) in MSI-negative ECs, while this inverse correlation disappeared in MSI-positive ECs. Furthermore, in MSI-positive ECs, 2 cases of concomitant RASSF1A methylation and KRAS mutation were found. Taken together, these results provide strong evidence that, in EC tumorigenesis, RASSF1A promoter hypermethylation is as important as KRAS mutations in activating the RAS pathway.

DNA Methylation↗

PubMed1996

Calculation of inversion half-lives of aryl propionic acid class nonsteroidal antiinflammatory drugs.

Although inversion of the R-enantiomers of the aryl propionic acid (APA) class of nonsteroidal antiinflammatory drugs (NSAIDs) in humans and other mammals has been known for more than 20 years, no satisfactory method has been developed for evaluating the half-life of the inversion process. This parameter is useful in assessing the pharmacodynamic contribution of the R-prodrug to the cyclooxygenase-inhibiting S-enantiomers. Further, it provides a similar means of evaluating the analgesic contributions of R-enantiomers to racemic mixtures. Using human and animal data, we have mathematically determined the inversion half-life (t1/2i) for ibuprofen, ketoprofen, and fenoprofen. The relation of the sensitivity of this value to the terminal half-life (t1/2) of the R-enantiomers of APA class drugs also is discussed.

Animals↗

PubMed2004

Intrinsic hematopoietic stem cell/progenitor plasticity: Inversions.

Traditional concepts indicate that stem cells give rise to progenitor cells in a hierarchical system. We studied murine engraftable stem cells (ESCs) and progenitors in in vitro and found that ESC and progenitors exist in a reversible continuum, rather then a hierarchy. B6.SJL and BALB/c marrow cells were serially cultured with thrombopoietin (TPO), FLT-3 ligand (FLT-3L), and steel factor through cell cycle. Progenitors (high-proliferative potential colony-forming cells (HPP-CFC) and colony-forming unit culture (CFU-c)) and ESC capacity was determined. The cell cycle status of purified lineage(negative)rhodamine(low)Hoechst(low) stem cells was determined under the same conditions using tritiated thymidine incorporation and cell counts. We found an inverse relationship between progenitors and ESC, which occurred during the first cell cycle transit and was reversible. We have termed these progenitor/stem cell inversions and found that these inversions were consistently seen at 28-32 h of culture, representing early S-phase. We observed 13 major reversible increases in progenitor numbers from one time-point to another during the first cell cycle transit; this was coupled with 11 major ESC decreases and in 2 instances ESC were at baseline. These studies indicate that primitive marrow cells reversibly shift from ESC to progenitors without differentiation occurring. They exist as a fluctuating continuum.

Animals↗

PubMed2003

Multislice double inversion-recovery black-blood imaging with simultaneous slice reinversion.

PURPOSE: To develop a technique for time-efficient multislice double inversion-recovery (DIR) black-blood imaging and to test its applicability and limitations for high-resolution imaging of carotid arteries. MATERIALS AND METHODS: A multislice DIR pulse sequence with fast spin-echo (FSE) readout was implemented on a 1.5 T magnetic resonance (MR) scanner. The principle of the method is that a slice-selective inversion in a DIR preparation reinverts an entire slice pack, and all slices are imaged within repetition time (TR). The number of slices acquired per TR (N) controls the inversion time (TI) to execute the readout for each slice at the zero-crossing point of blood. Multislice DIR images (TR/TE = 2500/9 msec) of carotid arteries were obtained with variable N = 2-8 from four subjects. The method was compared with the standard single-slice DIR and inflow saturation techniques. RESULTS: Multislice DIR with N = 2-6 provided similar flow suppression in carotid arteries as single-slice DIR. At all N = 1-8, blood suppression by DIR was significantly better than by inflow saturation. An additional limitation of multislice DIR was saturation of the signal from stationary tissues that worsened visualization of the vessel wall at N >or= 6. CONCLUSION: Multislice DIR provides up to eight-fold improvement of time-efficiency relative to single-slice DIR and high-quality blood suppression.

Adult↗

PubMedDate not supplied

Comparison of inversion recovery asymmetrical spin-echo EPI and gradient-echo EPI for brain motor activation study.

An inversion recovery asymmetric spin-echo (IR-ASE) echo-planar imaging (EPI) sequence has been developed for functional studies of the brain. This technique uses an 180 degrees inversion pulse with a long inversion time (TI) to suppress the pulsatile cerebrospinal fluid and an asymmetric spin-echo readout to obtain activation signals from brain capillaries. Because gradient-echo sequences are most sensitive to large vessels, motor cortex activation studies using a gradient-echo technique also were conducted for comparison with the IR-ASE method. The results suggest that the IR-ASE pulse sequence may be a useful complement to the gradient-echo technique for the study of neuronal activity of the human brain.

Brain Mapping↗

PubMed2006

Fluid-attenuated inversion-recovery SSFP imaging.

PURPOSE: To describe and evaluate a fast, fluid-suppressed 2D multislice steady-state free precession (SSFP) neuroimaging sequence. MATERIALS AND METHODS: We developed a fast fluid-attenuated inversion-recovery SSFP sequence for use in neuroimaging. The inversion time (TI) was optimized to yield good cerebrospinal fluid (CSF) suppression while conserving white matter (WM)/lesion contrast across a broad range of flip angles. Multiple SSFP acquisitions were combined using the sum-of-squares (SOS) method to maximize SNR efficiency while minimizing SSFP banding artifacts. We compared our fluid-attenuated inversion-recovery (FLAIR) SSFP sequence with FLAIR fast spin-echo (FSE) in both normal subjects and a volunteer with multiple sclerosis. SNR measurements were performed to ascertain the SNR efficiency of each sequence. RESULTS: Our FLAIR SSFP sequence demonstrated excellent CSF suppression and good gray matter (GM)/WM contrast. Coverage of the entire brain (5-mm slices, 24-cm FOV, 256 x 192 matrix) was achieved with FLAIR SSFP in less than half the scan time of a corresponding FLAIR FSE sequence with similar SNR, yielding improvements of more than 50% in SNR efficiency. Axial scans of a volunteer with multiple sclerosis show clearly visible plaques and very good visualization of brain parenchyma. CONCLUSION: We have demonstrated the feasibility of a very fast fluid-suppressed neuroimaging technique using SSFP.

Algorithms↗

PubMed1994

Astroglia-released factor shows similar effects as benzodiazepine inverse agonists.

Media conditioned by cultured neonatal cerebral cortex microexplants (CCM) or astrocytes (ACM) contain low molecular weight (< 1,000 Da) substance(s) which inhibits the gamma aminobutyric acid (GABA)-induced inward current recorded in cerebellar granule cells and hippocampal neurons in culture using the whole-cell patch-clamp technique. This effect is specific for CCM and ACM, as medium conditioned by PC12 cells (PC12CM) does not affect the GABA response of these cells. It is also specific for GABA-induced currents because glutamate-induced currents do not change either in amplitude or in shape in the presence of CCM or ACM. The inhibitory effect on the GABA response in cerebellar granule cells of both ACM and CCM could be suppressed by flumazenil, a specific benzodiazepine (BZD) antagonist and could be mimicked by two BZD inverse agonists. These data thus demonstrate the presence of a BZD inverse agonist-like activity in CCM and ACM. This effect of ACM on different neuronal cell types was heterogenous since no detectable effect could be observed on the GABA-induced current in GABA-responsive dorsal root ganglion (DRG) neurons, presumably reflecting a functional heterogeneity of the GABAA receptors present in these different neuronal subsets. By the release of such an endogenous BZD inverse agonist-like activity, glia cells could possibly modulate GABAA receptor-mediated responses.

Animals↗

PubMed1992

Variability of inversion of (R)-flurbiprofen in different species.

The anti-inflammatory activity of 2-arylpropionic acids like flurbiprofen appears to be due to the S enantiomers only. A unique characteristic of the metabolism of this class of drugs is inversion of configuration. The present study examines whether chiral inversion occurs after administration of the optically pure flurbiprofen enantiomers to various species (i.e., dogs, guinea pigs, rats, and gerbils). Concentrations of the enantiomers in plasma were analyzed by a stereoselective high-performance liquid chromatographic assay with a chiral alpha 1-acid glycoprotein column. Pharmacokinetic parameters of the flurbiprofen enantiomers were evaluated with a two-compartment computer model. Inversion of (R)-flurbiprofen to its optical antipode occurred to a variable extent in the dog [fraction inverted (Fi) = 0.39; n = 3] and the guinea pig (Fi = 1.00; n = 3) and to a much lower extent in the rat (Fi = 0.02; n = 3) and the gerbil (Fi = 0.05; n = 3). After intravenous administration of (S)-flurbiprofen to dogs, guinea pigs, rats, and gerbils, (R)-flurbiprofen was not detected in plasma (limit of quantification was 0.05 microgram/100 microL of plasma).

Animals↗

PubMed1995

Moment analysis of stereoselective biliary excretion and chiral inversion of ketoprofen enantiomers in perfused rat liver.

The stereoselective local disposition of ketoprofen was evaluated by the single-pass perfusion experiment following a bolus injection of R(-)- or S(+)-ketoprofen into the liver from the portal vein. The elution time profiles of enantiomers into the hepatic vein and the excretion time profiles into the bile were kinetically assessed by local moment analysis. The hepatic recovery ratios (FH) of both enantiomers were < 1%, and the mean hepatic transit times (tH) were approximately 7 s. After the injection of S-ketoprofen into the liver, the biliary excretion ratio (Fb) of total S-ketoprofen was 68% (15% S-ketoprofen and 53% glucuronide) and the mean biliary transit time (tb) of S-ketoprofen was 10 min. R-Ketoprofen inversion from S-ketoprofen was not observed in either the perfusate or in the bile. After the injection of R-ketoprofen, the Fb of total R-ketoprofen was 12% (3% R-ketoprofen and 9% glucuronide), and tb of R-ketoprofen was 8 min. The Fb of total S-ketoprofen inverted from R-ketoprofen was 24% (7% S-ketoprofen and 17% glucuronide), and the tb of inverted S-ketoprofen was 17 min. Forty-six percent of R-ketoprofen was inverted to S-ketoprofen during a single pass through the rat liver, and the mean inversion time was 7.5 min. It was concluded that the unidirectional chiral inversion of ketoprofen was stereospecific, and the hepatic uptake and biliary excretion were stereo-nonspecific.

Animals↗

PubMed2003

Frequency of recombinant and nonrecombinant products of pericentric inversion of chromosome 1 in sperm nuclei of carrier: by FISH technique.

Meiotic segregation products of carriers with pericentric inversion are very important for assessing the risk of unbalanced forms and appropriate genetic counseling. We investigated the incidence of recombinant and nonrecombinant products of chromosome 1 with pericentric inversion, in the sperm nuclei of the carrier by using triple color fluorescence in situ hybridization (FISH). The centromere specific and telomere specific probes for chromosome 1 were used. In the segregation analysis, 1,636 sperm nuclei were analyzed; 82.5% of the sperms were including normal or inverted chromosome 1, and the dup(p)/del(q) and del(p)/dup(q) recombinant products in sperm nuclei of our carrier were 8.7 and 7.3%, respectively. The number of recombinant products may be dependent on the formation of an inversion loop, which the number of the formation of chiasmata results in the different number of normal/balanced and recombinant products. The use of FISH, using different probe combination, in sperm nuclei has proved to be an accurate approach to determine the meiotic segregation patterns and could help to better establish a reproductive prognosis and genetic counseling.

Cell Nucleus↗