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PubMed2002

Sensitivity analysis of metabolic cascades catalyzed by bifunctional enzymes.

Covalent modification/demodification cycles are common in metabolism. When the modification and demodification steps are carried out by two independent enzymes, the degree of modification can be ultrasensitive to the total concentration of either catalyst. We recently showed that the degree of modification of a target molecule cannot exhibit ultrasensitivity to the free concentrations of effectors that decide whether a bifunctional enzyme acts as modifier or demodifier. However, here we can now demonstrate that the degree of modification of a target molecule can display ultrasensitivity to the total, rather than free, concentrations of such effectors. Our results clarify some general aspects of ultrasensitive responses to effectors, including competitive inhibitors, in mono-cyclic cascades.

Catalysis↗
PubMed1990

Rapid, sensitive analysis of protein mixtures by mass spectrometry.

We have developed a method for determining the molecular masses of proteins in complex mixtures by mass spectrometry. The method has the capacity to examine the components of mixtures without using any chromatographic separation steps and will tolerate relatively large amounts of buffers and inorganic contaminants. It allows the simultaneous determination of protein molecular masses from 1 to 40 kDa with an accuracy of +/- 0.01% and above 40 kDa with reduced accuracy. The lower limit for practical detection of a protein is a concentration of approximately 0.1 microM, and less than 1 microliter of such a solution is consumed. The analysis is very fast: less than 15 min is necessary to perform the complete analysis, including sample preparation, introduction into the mass spectrometer, mass spectrum collection, and data reduction. The mass spectrum that is obtained does not require elaborate interpretation because there is no fragmentation of the ionized protein (or protein subunit) molecule. Therefore, there is a one-to-one correspondence between the peaks in the mass spectrum and the proteins present in the original mixture. The spectra assume the appearance of chromatograms, with the abscissa being mass-to-charge ratio rather than chromatographic retention time.

Animals↗
PubMed1994

Risk of benzene-induced leukemia: a sensitivity analysis of the pliofilm cohort with additional follow-up and new exposure estimates.

This report updates the risk assessment by Crump and Allen (1984) for benzene-induced leukemia that was used by OSHA (1987) to support its reduction of the permissible exposure limit (PEL) to 1 ppm and that also was the basis for EPA's (1985) interim "unit risk" for benzene. The present study derives new risk estimates using data from follow-up through 1987 (whereas the earlier assessment only had follow-up available through 1978), and using new exposure estimates for this cohort developed by Paustenbach et al. (1992) that account for a number of factors that were unknown or not fully evaluated in earlier exposure assessments. There was a significant excess of acute myelocytic or acute monocytic leukemia (AMML, the only forms of acute nonlymphatic leukemia observed) in this cohort, and this end point also exhibited a strong dose-response trend. AMML was the only hematopoietic or lymphatic cancer that was clearly linked to benzene exposure. However, quantitative estimates of risk based on modeling either AMML or all leukemia differed by only 20%. Differences between the two Pliofilm plant locations in the occurrence of AMML were not statistically significant (.12 < or = p < or = .21) after differences in levels of benzene exposure were taken into account. The Paustenbach et al. exposures predicted a quadratic dose response, based on a measure of exposure that weighted intensity of exposure more heavily than duration of exposure. The best-fitting quadratic models predicted an additional lifetime risk of a benzene-related death from 45 yr of exposure to 1 ppm of between 0.020 and 0.036 per thousand. Statistical confidence intervals (90%) on these estimates were barely wide enough to include risk estimates based on linear dose response models. These linear models predicted risks of between 1.6 and 3.1 per thousand.

Adult↗
PubMed1994

Experimental design for parameter estimation through sensitivity analysis.

Parameter estimates can be obtained by fitting a numerical simulation model to experimental data, but these estimates may be biased and/or imprecise because of noise in the experimental data. Appropriate choice of experimental conditions, such as exposure or substrate concentrations and sampling times, can minimize the effect of experimental noise on parameter estimates, thus reducing bias and improving precision. This article describes a technique for selecting experimental (initial) conditions and measurement times for optimal parameter estimation. The technique makes use of a user-supplied mathematical simulation model for the process under study with a set of "current" parameter values specified. These "current" parameter values are the best that can be obtained using all available experimental data and/or literature information at the time when design calculations are performed. Early in a modeling study, the "current" parameter values will be tentative--based on a relatively small amount of information. Later in a study, the "current" parameter values may be known to reasonable accuracy, but final confirmation is desired. The technique uses the simulation model to calculate a numerical index for each possible experimental design. The numerical index, or Information Index, is a measure of the response of a simulation model to changes in parameter values, described by Kalogerakis and Luus (1983, 1984). The experimental design with the greatest value of Information Index is the one under which parameters can be most precisely estimated. Computation of the Information Index, described in detail, can be somewhat complicated, depending on the software available. The results, however, are simple to interpret and provide valuable information on the quality of alternate proposed experiments. The technique is applicable to a broad range of dynamical systems. Its use is demonstrated by application to a simulation model being developed to describe the in vitro metabolism of benzene by mouse liver microsomes.

Animals↗
PubMed1999

Simple and sensitive analysis of nereistoxin and its metabolites in human serum using headspace solid-phase microextraction and gas chromatography-mass spectrometry.

A simple method for the analysis of nereistoxin and its metabolites in human serum using headspace solid-phase microextraction (SPME) and gas chromatography-mass spectrometry (GC-MS) is developed. A vial containing a serum sample, 5M sodium hydroxide, and benzylacetone (internal standard) is heated to 70 degrees C, and an SPME fiber is exposed for 30 min in the headspace of the vial. The compounds extracted by the fiber are desorbed by exposing the fiber in the injection port of the GC-MS. The calibration curves show linearity in the range of 0.05-5.0 micrograms/mL for nereistoxin and N-methyl-N-(2-methylthio-1-methylthiomethyl)ethylamine, 0.01-5.0 micrograms/mL for S,S'-dimethyl dihydronereistoxin, and 0.5-10 micrograms/mL for 2-methylthio-1-methylthiomethylethylamine in serum. No interferences are found, and the analysis time is 50 min for one sample. In addition, this proposed method is applied to a patient who attempted suicide by ingesting Padan 4R, a herbicide. Padan 4R contains 4% cartap hydrochloride, which is an analogue of nereistoxin. Nereistoxin and its metabolites are detected in the serum samples collected from the patient during hospitalization. The concentration ranges of nereistoxin in the serum are 0.09-2.69 micrograms/mL.

Adult↗
PubMedDate not supplied

Simultaneous and sensitive analysis of THC, 11-OH-THC, THC-COOH, CBD, and CBN by GC-MS in plasma after oral application of small doses of THC and cannabis extract.

Besides the psychoactive Delta(9)-tetrahydrocannabinol (THC), hashish and marijuana as well as cannabis-based medicine extracts contain varying amounts of cannabidiol (CBD) and of the degradation product cannabinol (CBN). The additional determination of these compounds is interesting from forensic and medical points of view because it can be used for further proof of cannabis exposure and because CBD is known to modify the effects of THC. Therefore, a method for the simultaneous quantitative determination of THC, its metabolites 11-hydroxy-Delta(9)-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THC-COOH), CBD and CBN from plasma was developed. The method was based on automatic solid-phase extraction with C(18) ec columns, derivatization with N,O-bistrimethylsilyltrifluoroacetamide (BSTFA), and gas chromatography-electron impact ionization-mass spectrometry (GC-EI-MS) with deuterated standards. The limits of detection were between 0.15 and 0.29 ng/mL for THC, 11-OH-THC, THC-COOH, and CBD and 1.1 ng/mL for CBN. The method was applied in a prospective pharmacokinetic study after single oral administration of 10 mg THC alone or together with 5.4 mg CBD in cannabis extract. The maximum plasma concentrations after cannabis extract administration ranged between 1.2 and 10.3 ng/mL (mean 4.05 ng/mL) for THC, 1.8 and 12.3 ng/mL (mean 4.9 ng/mL) for 11-OH-THC, 19 and 71 ng/mL (mean 35 ng/mL) for THC-COOH, and 0.2 and 2.6 ng/mL (mean 0.95 ng/mg) for CBD. The peak concentrations (mean values) of THC, 11-OH-THC, THC-COOH, and CBD were observed at 56, 82, 115, and 60 min, respectively, after intake. CBN was not detected. Caused by the strong first-pass metabolism, the concentrations of the metabolites were increased during the first hours after drug administration when compared to literature data for smoking. Therefore, the concentration ratio 11-OH-THC/THC was discussed as a criterion for distinguishing oral from inhalative cannabis consumption.

Administration, Oral↗
PubMedDate not supplied

Rapid and sensitive analysis of morphine in serum by reversed-phase high performance liquid chromatography with electrochemical detection.

A method is described for the determination of morphine in serum. Separation and quantitation are performed by reversed-phase high performance liquid chromatography with electrochemical detection. A sample size of 100 microL or less is required for detection of concentrations as low as 1 to 2 ng/mL. In trials with standard solutions, recovery was 75%. The between-run and within-run coefficients of variation were 7.3% (over the range of 5 to 200 ng/mL) and 9.1% (at 5 ng/mL), respectively.

Animals↗
PubMed1984

Conformational change of Ca2+,Mg2+-adenosine triphosphatase of sarcoplasmic reticulum upon binding of Ca2+ and adenyl-5'-yl-imidodiphosphate as detected by trypsin sensitivity analysis.

Ca2+-Mg2+-ATPase of sarcoplasmic reticulum was subjected to trypic digestion under various conditions and the cleavage patterns were compared. The first tryptic cleavage to yield the NH2-terminal A-fragment (Mr approximately equal to 55,000) and COOH-terminal B-fragment (Mr approximately equal to 45,000) [Thorley-Lawson, D.A. & Green, N.M. (1977) Biochem. J. 167, 739-748] was little affected by adding ligands such as Ca2+ and AMP-P(NH)P. On the other hand, subsequent splitting of A-fragment into A1 (Mr approximately equal to 30,000) and A2 (Mr approximately equal to 20,000), and further cleavages giving rise to three smaller fragments of Mr approximately equal to 27,000-28,000 (A1a, A1b, and C) [Saito, K., et al. (1984) J. Biochem. 95, 1297] were profoundly affected by these ligands. A difference in cleavage sites was noted depending on Ca2+ ion concentration; thus, A1b and C were the major components remaining after digestion in the presence and absence of Ca2+, respectively. AMP-P(NH)P markedly stabilized both A1 and A2 fragments, but the effect was much more prominent when Ca2+ was simultaneously present on the transport site. These findings suggest that conformational changes of the ATPase molecule upon binding of Ca2+, AMP-P(NH)P, or both are accompanied by corresponding changes in the susceptibility to tryptic digestion. Fragments A1 and A2 were both quite stable and fragmentation did not proceed beyond A1, when sarcoplasmic reticulum membranes were treated with trypsin at 0 degrees C. Significant further fragmentation of A1 was observed only above 20 degrees C, suggesting a conformational transition of the ATPase protein around that temperature.

Adenosine Triphosphate↗