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PubMed2001

Chromatographic characterization of molecularly imprinted microspheres for the separation and determination of trimethoprim in aqueous buffers.

Molecularly imprinted microspheres (MIMs) against trimethoprim (TMP), prepared by aqueous microsuspension polymerization, bound strongly to TMP, by electrostatic and other non-covalent interactions. The effects of pH, kind and ionic strength (I) of buffer on capacity factors (k') have been discussed in detail. The capacity factors for TMP increased with increasing pH of both acetate and phosphate buffers. The effects of ionic strength on capacity factors were very substantial and the linear relationship between logk' and logI was described by the equation logk'=0.3162-0.4420logI with R=-0.9995. The results showed that pH 3.5 acetate buffer (0.05 mol L(-1)) containing 0.1 mol L(-1) sodium chloride and a 1:9 ratio of buffer to methanol were the optimum conditions for separation and determination of TMP. The calibration plot of peak area against concentration was linear with R=0.9979.

Biosensing Techniques↗
PubMed2003

Trimethoprim induces heat shock proteins and protein aggregation in E. coli cells.

Trimethoprim (TMP), an inhibitor of dihydrofolate reductase, decreases the level of tetrahydrofolate supplying one-carbon units for biosynthesis of nucleotides, proteins, and panthotenate. We have demonstrated for the first time that one of the effects of the TMP action in E. coli cells is protein aggregation and induction of heat shock proteins (Hsps). TMP caused induction of DnaK, DnaJ, GroEL, ClpB, and IbpA/B Hsps. Among these Hsps, IbpA/B were most efficiently induced by TMP and coaggregated with the insoluble proteins. Upon folate stress, deletion of the delta ibpA/B operon resulted in increased protein aggregation but did not influence cell viability.

Escherichia coli↗
PubMed1991

Circulatory and metabolic changes in the brain during induced hypotension--comparison among trimetaphan, glycerin trinitrate and prostaglandin E1.

Induced hypotension was carried out using trimetaphan (TMP), glycerin trinitrate (GTN) and prostaglandin E(1) (PGE(1)) in 45 patients received elective abdominal surgery under anesthesia with enflurane in N(2)O/O(2) in order to evaluate and compare the effects of these three agents on cerebral circulation and metabolism. Upon reduction of mean arterial blood pressure to 60-65 mmHg, cerebral blood flow decreased in the TMP and GTN groups but increased in the PGE(1) group. The changes were quite proportional to those in cardiac index in the three groups. Cerebral oxygen consumption decreased only in the TMP group. Changes in cerebrospinal fluid pressure were not in parallel with those in cerebral blood flow. The former decreased slightly in the TMP group but increased in the GTN and PGE(1) groups. These results offered a great caution for induction of artificial hypotension using these agents.

Journal Article↗
PubMed1984

A method to reduce interference by sucrose in the detection of thiobarbituric acid-reactive substances.

A thiobarbituric acid (TBA) reaction for measuring lipid peroxidation products was evaluated for interference by several ingredients commonly used in solutions to prepare or analyze tissue homogenates or subcellular organelles. These included sucrose (up to 100 mM final concentration in the assay medium), Tris-maleate (up to 40 mM), imidazole (up to 20 mM), inorganic phosphate (up to 10 mM), and 4- morpholinepropanesulfonic acid (up to 20 mM). When the samples were heated at 95 degrees C as recommended in some procedures, only sucrose significantly affected color development. Sucrose concentrations as low as 10 mM significantly increased absorbance at 532 nm of aqueous tetramethoxypropane (TMP) standards, and so the assay could not be applied reliably to tissue samples prepared in sucrose. Sucrose interference was only partially reduced by subsequent organic extraction (n-butanol plus pyridine), with measured absorbances remaining significantly greater (50-100%) than sucrose-free controls at sucrose concentrations of 20 mM or more. Modifying the assay to include sucrose in blanks and TMP standards failed to adequately correct for interference when the absorbance of unextracted (aqueous) solutions was measured. Further modification by adding sucrose to blanks and TMP standards, followed by butanol-pyridine extraction, gave standard curves that were linear, through the origin, and had slopes equivalent to those of sucrose-free standards. This modification enabled almost complete recovery (average 2% error) of known amounts of TMP added to aliquots of tissue homogenates containing amounts of sucrose that otherwise significantly interfered. Also, with the modified method the content of TBA-reactive substances in tissues homogenized in sucrose was found to be not significantly different from that measured in tissues homogenized in a noninterfering substance, KCl.

Animals↗
PubMed1985

Identification of urinary metabolites of the nephrotoxic hydrocarbon 2,2,4-trimethylpentane in male rats.

The compound 2,2,4-trimethylpentane (2,2,4 TMP) is reported to be especially potent in inducing kidney lesions in male rats (1,2). Although the pathology produced by 2,2,4 TMP has been examined (1), there are no reports concerning the metabolism of 2,2,4 TMP by the male rat. The eight principal urinary metabolites of 2,2,4 TMP found in the urine of Fischer 344 male rats are: 2,2,4-trimethyl-1-pentanol, 2,4,4-trimethyl-1-pentanol, 2,4,4-trimethyl-2-pentanol, 2,2,4-trimethyl-1-pentanoic acid, 2,4,4-trimethyl-1-pentanoic acid, 2,4,4-trimethyl-2-hydroxy-1-pentanoic acid, 2,2,4-trimethyl-5-hydroxy-1-pentanoic acid and 2,4,4-trimethyl-5-hydroxy-1-pentanoic acid.

Animals↗
PubMed1989

Effects of nuclear isolation on psoralen affinity for chromatin.

We have tested the effects of nuclear isolation on intercalation of TMP (a psoralen) at specific sequences and in total DNA of cultured human cells. DNA in nuclei photobound about 20% more TMP than in cells and about 10% as much as purified DNA. In contrast, a transcribed ras gene and a randomly selected polymorphic sequence each bound about 20% more TMP than total DNA in cells. However, in nuclei, as in purified DNA, both sequences were just as sensitive as total DNA. Apparently, chromatin in cells exists within diverse TMP-binding environments and some of this diversity was lost upon nuclear isolation.

Calorimetry↗
PubMed1984

Nervous tissue thiamine metabolism in vivo. I. Transport of thiamine and thiamine monophosphate from plasma to different brain regions of the rat.

The transport of thiamine (T) and thiamine monophosphate (TMP) across the blood-brain barrier was measured in vivo in the rat. Different doses of [14C]T (15-550 nmol) and [14C]TMP (11-110 nmol) were injected into the femoral vein. The content of T and its phosphoesters in blood and brain tissue (cerebellum, pons, medulla and cerebral cortex) 20 s after the injection was determined radiometrically after electrophoretic separation. Blood flow and blood volume in the same regions of the brain was also determined. Both T and TMP entered rapidly the cerebral tissue, where they were found chemically unmodified. The cerebral tissue extracted less than 7% of plasma T. At physiological plasma T concentrations, the rate of transport ranged from 0.43 to 0.65 nmol X g-1 X h-1 with only minor differences among the various regions. T was transported into the nervous tissue by two separate mechanisms: one saturable, that at physiological plasma T levels accounted for 95% (cerebellum) to 91% (cerebral cortex) of the total T taken up, and one non-saturable, that was most efficient in the cerebral cortex. The Km (half-saturation constant) of the former transport mechanism ranged from 1.95 to 2.75 nmol X ml-1 in the 4 areas investigated. Vmax (maximal transport rate) values ranged from 6 to 9 nmol X g-1 X h-1, the highest value being found in the cerebellum. The overall transport rate of TMP was on average 5-10 times as low as that of T and also showed a saturable and a non-saturable component. Both components were slower than those observed for T.

Animals↗
PubMed1990

Androgen receptors are differentially distributed between right and left cerebral hemispheres of the fetal male rhesus monkey.

In humans there are apparent sex differences in verbal and spatial abilities as well as several cortical pathologies. These differences may arise as the result of prenatal androgen exposure and its effect on the development of the cerebral cortex. With this in mind, we have examined androgen receptor (AR), aromatase (AROM) and 5 alpha-reductase (5 alpha R) levels in the cerebral cortex of Day 70 male and female fetal rhesus monkeys (Macaca mulatta). Receptor and enzyme levels were evaluated in both right (Rt) and left (Lft) temporal (TMP) and frontal (FR) lobes of the cerebral cortex. AR levels in FR-Rt of male subjects were higher than levels in FR-Lft (for each and every subject, P less than 0.05), while in females, there was no consistent pattern in the distribution of the receptor between the two sides of FR. In contrast, AR values in TMP-Lft of male subjects were consistently higher than in TMP-Rt (P less than 0.05). As with the FR, females exhibited no consistent pattern in the distribution of AR between the two TMP sides. AROM and 5 alpha R levels were similar, regardless of sex, between both sides of the two cortical lobes indicating that the AR distribution pattern is not a general biochemical phenomenon. The differential cortical distribution of AR in fetal males versus females lends support to the hypothesis that prenatal androgens from the fetal testes may effect the differentiation of sexually dimorphic, side-specific cortical activity.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1985

Effects of subchronic treatment with O,O,S-trimethyl phosphorothioate on cellular and humoral immune response systems.

The effect of a 14-day treatment with low doses of O,O,S-Trimethyl phosphorothioate (OOS-TMP), an impurity in technical malathion, on the generation of cell-mediated and humoral immune responses was examined in female C57B1/6 mice. At a dose of 0.5 mg/kg/day OOS-TMP, the generation of antibody-secreting cells to sheep red blood cells (SRBC), the production of interleukin 2 (IL-2), and proliferative responses to the mitogens concanavalin A (Con A) and lipopolysaccharide (LPS) were elevated. In contrast, the cytotoxic T-lymphocyte (CTL) response to alloantigen was unchanged. At 5.0 mg/kg/day OOS-TMP, both the CTL and specific antibody response were unchanged, but all other immune parameters examined were elevated. Data from cell separation and reconstitution experiments indicated that both macrophages and B cells were affected by this treatment regime. These data suggest that long-term exposure to low amounts of OOS-TMP may enhance the ability of an animal to generate an immune response.

Administration, Oral↗
PubMed1986

Assessment of unscheduled and replicative DNA synthesis in hepatocytes treated in vivo and in vitro with unleaded gasoline or 2,2,4-trimethylpentane.

In a recent chronic inhalation exposure study, unleaded gasoline (UG) produced kidney tumors in male rats and liver tumors in female mice, but did not increase the incidence of liver tumors in male mice or rats of either sex. To examine the possible basis for this pattern of hepatocarcinogenesis, unscheduled DNA synthesis (UDS) as an indicator of genotoxic activity and replicative DNA synthesis (RDS) as an indicator of cell proliferation were measured in rat and mouse hepatocytes following in vivo and in vitro exposures to UG and 2,2,4-trimethylpentane (TMP), a nephrotoxic component of UG. Primary hepatocyte cultures, prepared from cells isolated from Fischer-344 rats, B6C3F1 mice, or human surgical material, were incubated with [3H]thymidine and the test agent. UDS was measured by quantitative autoradiography as net nuclear grains (NG). By similar methods, UDS and RDS (S-phase cells) were measured in hepatocytes isolated from rats and mice treated by gavage with TMP (500 mg/kg) or UG (100 to 5,000 mg/kg). A dose-related increase in UDS activity was observed in rat hepatocytes treated in vitro with 0.05 to 0.10% (v/v) UG. These doses were, however, toxic in both mouse and human hepatocyte cultures. Weak UDS activity was observed in hepatocytes isolated from male and female mice treated 12 hr previously with UG. No UDS was induced in rat hepatocytes treated in vivo or in vitro with TMP. Twenty- and fourfold increases in the percentage of cells in S-phase were observed 24 hr after treatment with TMP in male and female mice, respectively, as compared to a fivefold increase in male rats. UG increased the percentage of S-phase cells in male mice by ninefold but failed to induce RDS in females. Thus, there appears to be genotoxic compounds in UG that can be detected in cultured hepatocytes and in the livers of exposed mice. The lack of UDS activity in rat liver was consistent with the reported lack of liver tumors in chronically exposed rats. However, neither the UDS nor the RDS responses in mice exposed by gavage correlated to the sex-specific pattern of liver tumors observed in the 2-year bioassay.

Animals↗
PubMed1989

Elevated proliferation of proximal tubule cells and localization of accumulated alpha 2u-globulin in F344 rats during chronic exposure to unleaded gasoline or 2,2,4-trimethylpentane.

In order to better characterize the pathogenesis of alpha 2u-globulin (alpha 2uG) nephropathy, cell proliferation was quantitated within the three proximal tubule segments of the kidney (P1, P2, and P3) and proximal tubule segments affected by chronic progressive nephrosis (CPN) in male and female F344 rats exposed to 10, 70, or 300 ppm unleaded gasoline (UG) or 50 ppm 2,2,4-trimethylpentane (TMP) from 3 to 50 weeks. The P2 segment of male rats exposed to UG or TMP responded with dose-related increases in cell turnover (up to 11-fold) that persisted during chronic exposure. This proliferative response closely paralleled the extent and severity of immunohistochemically detectable alpha 2uG in the P2 segment. Neither alpha 2uG nor cytotoxicity was evident in cells of the P1 or P3 segment; however, cell proliferation was increased (up to 8-fold) for up to 22 weeks of exposure in the P3 segment. Increased numbers of proximal tubules affected by CPN were found in males exposed to UG or TMP for 22 or 48 weeks, compared to controls. These lesions contained epithelial cells that were highly proliferative. Control or treated female rats exhibited neither alpha 2uG nephropathy nor increases in P2 or P3 cell turnover, and the extent of CPN was greatly reduced as compared to male rats. The results of this and related studies suggest that chronic cell proliferation associated with alpha 2uG nephropathy and CPN in male rats exposed to UG or isoparaffinic components of UG, such as TMP, may be responsible for the sex- and species-specific nephrocarcinogenic effects of UG.

Acute Kidney Injury↗
PubMed1989

Low levels of herpes simplex virus thymidine- thymidylate kinase are not limiting for sensitivity to certain antiviral drugs or for latency in a mouse model.

Herpes simplex virus mutant KG111 contains a nonsense mutation at codon 44 of the viral thymidine kinase (tk) gene and produces low amounts of a truncated tk polypeptide. We tested mutant KG111 and related viruses that specify varying amounts of similar truncated tk polypeptides for their sensitivities to antiviral nucleoside analogs at different temperatures using plaque reduction assays. The results of these assays showed that the nonsense mutation confers high resistance to bromovinyldeoxyuridine (BVdU) at any temperature and temperature-dependent resistance to acyclovir (ACV), buciclovir (BCV), ganciclovir (DHPG), and fluoroiodoarabinouracil (FIAU). Above relatively low threshold levels of tk that varied depending on the drug tested, viruses exhibited full sensitivity to ACV, BCV, DHPG, and FIAU at 34 degrees. Below these threshold levels, however, decreases in drug sensitivity were linear with decreases in tk levels, forming the basis of a pharmacological assay for tk gene expression. Studies of thymidine (TdR) anabolism in infected 143 tk-cells showed that when high TdR concentrations were added to the medium, KG111 directed thymidine monophosphate (TMP) formation at rates consonant with the amount of tk polypeptide produced by the mutant. When low concentrations to TdR were added to the medium, however, KG111 directed TMP formation at a rate similar to that directed by wild-type virus, indicating that the truncation of the tk polypeptide had little or no effect on tk activity at 34 degrees. Subsequent anabolism to thymidine diphosphate and thymidine triphosphate was reduced in KG111-infected cells, indicating a defect in TMP kinase activity that explains this mutant's resistance to BVdU. Despite the low levels of tk and TMP kinase activity expressed by KG111, this mutant established reactivatable latent infections as efficiently as wild-type virus in a mouse model.

Acyclovir↗
PubMed1985

Investigations into the mechanism of immunosuppression caused by acute treatment with O,O,S-trimethyl phosphorothioate. II. Effect on the ability of murine macrophages to present antigen.

Acute administration of 10 mg/kg O,O,S-trimethyl phosphorothioate (OOS-TMP) for 24 h has been shown to suppress the in vitro generation of cytotoxic T lymphocyte responses and antibody-secreting cells to sheep red blood cells and to increase interleukin-2 production. Macrophages were shown to be the splenic cell population most affected by OOS-TMP pretreatment. In this report, the ability of macrophages from OOS-TMP-treated animals to function in antigen presentation was shown to be significantly decreased. In addition, macrophages from treated animals had increased phagocytic capability and interleukin-l production. However, the percentage of Ia-positive macrophages present in splenic populations was decreased following OOS-TMP treatment. A decrease in antigen presenting ability and the number of Ia-positive macrophages may explain the reversible suppression in cytotoxic T lymphocytes and antibody responses reported previously.

Animals↗
PubMed1996

Leukocyte transmembrane potential in bipolar illness.

Abnormalities in ion regulation and distribution are commonly reported in bipolar disorder. In an effort to determine if these alter cellular physiological function, we determined the transmembrane potential (TMP) in mononuclear leukocytes from normal individuals and patients with bipolar illness either during normal phase or manic and hypomanic episodes. TMP was analyzed by flow cytometry using dihexyloxacarbocyanine iodide (DIOC6(3)), a cationic potential sensitive fluorescent dye. A normal range was established from measurements on leukocytes from 5 control individuals. TMP of manic and hypomanic patients was significantly hyperpolarized (P = 0.0036). The TMP of euthymic bipolar individuals was not different from normal controls. Pathologic moods in bipolar illness may be associated with altered cellular membrane physiology.

Acute Disease↗
PubMed1983

Comparative bacterial mutagenicity studies with 8-methoxypsoralen and 4,5',8-trimethylpsoralen in the presence of near-ultraviolet light and in the dark.

2 strains of S. typhimurium, TA98 and TA100, and 2 strains of E. coli, WP2(pKM101) and WP2uvrA-(pKM101) were used to study mutagenesis by 8-methoxypsoralen (8-MOP) and 4,5',8-trimethylpsoralen (4,5',8-TMP) in the dark and in the presence of near-ultraviolet (NUV) light both without metabolic activation and with rat-liver S9 at 3 levels (4, 10 and 30% in standard cofactors). The S9-independent base substitution mutagenic activity of 8-MOP plus NUV light was confirmed in WP2(pKM101), and a similar activity was seen for 4,5',8-TMP, although neither substance was active in TA100. The frameshift mutagenic activity of 8-MOP in the dark in TA98 was not confirmed despite histidine levels which would ensure DNA replication, but this may be due to the lower concentrations of 8-MOP achieved in the common solvent system adopted. Both 8-MOP and 4,5',8-TMP were mutagenic in WP2uvrA-(pKM101) after microsomal activation, and the responses were similar whether experiments were conducted in the dark or in NUV light. In view of the oral administration of 8-MOP to psoriasis patients, this finding may be of relevance in risk assessment, and tends to suggest that topical application of 4,5',8-TMP to psoriatic patients may present reduced risk of malignant disease.

Animals↗
PubMed1988

Two DNA endonuclease activities from normal human and xeroderma pigmentosum chromatin active on psoralen plus ultraviolet light treated DNA.

DNA endonuclease activities from the chromatin of normal human and xeroderma pigmentosum, complementation group A (XPA), lymphoblastoid cells were examined on DNA treated with 8-methoxypsoralen (8-MOP) or 4,5',8-trimethylpsoralen (TMP) plus long wavelength ultraviolet (UVA) light, which produce monoadducts and DNA interstrand cross-links, and angelicin plus UVA light, which produces mainly monoadducts. 9 chromatin-associated DNA endonuclease activities were isolated from normal and XPA cells and assayed for activity on PM2 bacteriophage DNA that had been treated with 8-MOP or TMP in the dark and then exposed to UVA light. Unbound psoralen was removed by dialysis and a second dose of UVA light was given. Cross-linking of DNA molecules was confirmed by alkaline gel electrophoresis. In both normal and XPA cells, two DNA endonuclease activities were found which were active on 8-MOP and TMP plus UVA light treated DNA. One of these endonuclease activities, pI 4.6, is also active on intercalated DNA and a second one, pI 7.6, is also active on UVC (254 nm) light irradiated DNA. The major activity against angelicin plus UVA light treated DNA in both normal and XPA cells was found in the fraction, pI 7.6. The levels of activity of both of these fractions on all 3 psoralen-damaged DNAs were similar between normal and XPA cells. These results indicate that in both normal and XPA cells there are at least two different DNA endonucleases which act on both 8-MOP and TMP plus UVA light treated DNA.

Cell Line↗
PubMed1995

Use of the Escherichia coli chromosomal DHFR gene as selection marker in mammalian cells.

The folA gene, the chromosomal dhfr gene of Escherichia coli, was engineered for expression in mammalian cells. In contrast to plasmid-derived bacterial dhfr genes previously used as selection markers in mammalian cells, the folA gene product is inhibitable by methotrexate (MTX) and trimethoprim (TMP). Therefore, this dhfr may present an alternative to mammalian dhfr species currently used as amplifiable selection markers. Transfected E. coli folA dhfr could complement the lack of endogenous DHFR in Chinese hamster ovary (CHO) cells lacking a functional dhfr gene. Both MTX and TMP inhibited growth of E. coli folA dhfr-transfected CHO cells. Expression of E. coli folA DHFR could be visualized by incubating the transfected cells with a fluorescent methotrexate derivative (F-MTX). Binding of F-MTX to E. coli folA DHFR was inhibitable as by both MTX and TMP, whereas MTX but not TMP blocked binding of F-MTX to recombinant mouse DHFR.

Animals↗
PubMed1995

The simian immunodeficiency virus transmembrane protein is poorly immunogenic in inactivated virus vaccine.

The transmembrane proteins (TMP) of immunodeficiency lentiviruses are primary candidates for inclusion in AIDS vaccines, the design and testing of which is facilitated by the SIV-macaque infection model. Antibody responses to linear determinants in the SIVmac TMP were investigated in rhesus macaques either infected with the SIVmac J5 molecular clone or vaccinated with partially purified, formalin-inactivated SIVmac. Infected animals were shown to recognise predominantly four regions in the external domain and three regions in the internal domain of the TMP defined by a series of nominally 20mer overlapping peptides. In contrast SIV vaccinates had extremely restricted and weak antibody responses to the TMP, indicating a selective loss of immunogenicity of this component in the vaccine.

Amino Acid Sequence↗