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  • 1
    Electronic Resource
    Electronic Resource
    Mutant genes of cytochrome P-450IID6, glutathione S-transferase class Mu, and arylamine N-acetyltransferase in lung cancer patients (1992)
    Springer
    Journal of molecular medicine 70 (1992), S. 307-319 
    Details
    ISSN: 1432-1440
    Keywords: Pharmacogenetics ; Cancer epidemiology ; Lung cancer ; Polymerase chain reaction ; Restriction fragment length polymorphism ; Cytochrome P-45011136 ; Glutathione S-transferase ; Arylamine N-acetyltransferase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Epidemiological studies suggested a protective effect of certain phenotypes of polymorphic foreign-compound-metabolizing enzymes in some types of cancer. Poor metabolizers (PM) of debrisoquine 4-hydroxylase (cytochrome P-450IID6, CYP2D6) were found to be underrepresented among patients with lung cancer. Recent advances in molecular genetic characterization of CYP2D6, glutathione S-transferase (GST) class Mu, and arylamine N-acetyltransferase enabled genotypical determination of mutant alleles in lung cancer patients. Restriction fragment length polymorphism (RFLP) with a cDNA gene probe of CYP2D6 was analyzed in 79 lung cancer patients who were phenotyped with debrisoquine. Mutant alleles were detected by allele-specific polymerase chain reaction (PCR). In the same individuals, genotype of GST class Mu was analyzed by PCR and correlated with ex vivo activity of glutathione conjugation towards trans-stilbene oxide. RFLP patterns allowed discrimination between the slow and fast genotype of N-acetyltransferase as well as the heterozygotes. Three phenotypical PMs of debrisoquine (3.8%) were confirmed by PCR and RFLP. No PM could be unambiguously recognized only by RFLP patterns. The PMs were characterized by PCR and RFLP as carriers of the 29B/29B (n=1), 29A/29B (n=1), and 29A/44 (n = 1) mutant alleles. Higher debrisoquine hydroxylase activities were found in the homozygous EMs, who possess two active genes, as compared to heterozygous EMs, who have only one active gene. The patients with phenotypically impaired GST Mu activity were confirmed as such by PCR. A complete correspondence between phenotyping of N-acetyltransferase (with caffeine) and genotyping was found. The new genetic techniques proved to be powerful tools for molecular-epidemiological studies aimed at establishing host factors of cancer susceptibility.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00184667
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  • 2
    Electronic Resource
    Electronic Resource
    Cyclosporin drug monitoring: Comparison of four immunoassays and HPLC (1989)
    Springer
    Journal of molecular medicine 67 (1989), S. 438-441 
    Details
    ISSN: 1432-1440
    Keywords: Cyclosporin ; Drug monitoring ; Immunoassay ; High-performance liquid chromatography ; Renal transplantation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Cyclosporin blood trough levels were measured with four different immunoassays and high-performance liquid chromatography in 12 patients receiving low-dose steroids and CsA after kidney transplantation. These patients represent a selection with an uncomplicated posttransplant course and received no drugs with a known influence on CsA pharmacokinetics. The use of specific antibodies against the parent drug yielded levels comparable to those detected by HPLC. CsA levels measured with nonspecific antibodies exceeded those measured with specific ones by a factor of two to three. All immunoassay-detected CsA levels correlated significantly with the HPLC-determined CsA levels. In addition, blood levels of the CsA metabolites 1, 17, 18, and 21 were determined by HPLC. In one additional patient, who was under tuberculostatic treatment and had a transitory deterioration of liver function, levels of nonspecificantibody-determined CsA rose, as confirmed by rising levels of metabolite 17, while those of the parent drug fell. We conclude that routine drug monitoring should include at least one immunoassay with a specific antibody detecting the unchanged CsA, and a supplementary immunoassay with a nonspecific antibody detecting a composition of cross-reacting metabolites plus the unchanged substance. If available, HPLC should be used to confirm levels of CsA and its metabolites in patients with suspected alteration of their CsA metabolism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01725139
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  • 3
    Electronic Resource
    Electronic Resource
    Polymorphisms in the human CYP1A1 gene as susceptibility factors for lung cancer: exon-7 mutation (4889 A to G), and a T to C mutation in the 3′-flanking region (1994)
    Springer
    Journal of molecular medicine 72 (1994), S. 240-248 
    Details
    ISSN: 1432-1440
    Keywords: Cytochrome P-450 ; CYP1A1 ; Polymorphism ; Lung cancer ; Polymerase chain reaction ; Cancer epidemiology ; Risk factor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Genetic differences in the metabolism of carcinogens may codetermine individual predisposition to cancer. Cytochrome P-4501A1 (CYP1A1) metabolically activates precarcinogens in cigarette smoke, such as benzo(a)pyrene, which is also an inducer of CYP1A1. Two point mutations have been reported, m1 in the 3′-flanking region (6235T to C), and m2 within exon 7 (4889A to G), the latter leading to an isoleucine to valine exchange. In the Japanese population ml and m2 are correlated with lung cancer, suggesting an increased susceptibility to cigarette smoking related lung cancer. We studied 142 lung cancer and 171 reference patients in an ethnically homogeneous German group for m1 and m2 mutations by restriction fragment length polymorphism and allele-specific polymerase chain reaction, respectively. No statistically significant difference was found in the distribution of m1 alleles between lung cancer and controls; the frequency was 8.5% and 7.3% of the alleles, respectively (odds ratio = 1.17). A trend to an overrepresentation of ml alleles was observed among 52 squamous cell carcinoma patients (odds ratio = 1.65). In contrast, the frequency of m2 alleles in lung cancer patients was twofold higher (6.7%) than in the reference group (3.2%; odds ratio = 2.16; 95% confidence limits 0.96–5.11, P = 0.033); the odds ratio of m2 alleles in squamous cell carcinoma was 2.51 (95% confidence limits 0.85–7.05, P = 0.05). There was a close genetic linkage of m2 to m1 (10 of 11 reference patients), but a significantly higher number of cancer patients showed no linkage compared to the controls (odds ratio = 8.89, 95% confidence limits 0.83–433, P = 0.04). Thus no association was found between presence of ml alleles and lung cancer, but, in contrast, m2 alleles proved as a hereditary risk factor, especially if not linked with m1 alleles.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00189321
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  • 4
    Electronic Resource
    Electronic Resource
    Evaluation of proposed sulphoxidation pathways of carbocysteine in man by HPLC quantification (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 387-392 
    Details
    ISSN: 1432-1041
    Keywords: Carbocysteine ; pharmacogenetics ; drug metabolism ; sulphoxidation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A quantitative study has been made of the metabolism of S-carboxymethyl-L-cysteine (CMC) and its sulphoxides in volunteers by HPLC. Precolumn derivatization was applied prior to gradient reversed phase HPLC separation and fluorescence detection. For CMC and its metabolites containing a primary amino group the reagent 9-fluorenylmethylchloroformate was used. The other metabolites of CMC were derivatized at their carboxylic group with 1-pyrenyldiazomethane to give stable fluorescent products. Urine samples were collected for 8 h after oral administration of 1.125 g CMC to 33 healthy volunteers. Elimination of CMC in urine as sulphoxides did not account for more than 1% of the dose in any of the volunteers. Thus, CMC-sulphoxide metabolites are not quantitatively important. Recovery of the original substance in 8-hour urines ranged from 10 to 30% and a further 2 to 20% was recovered as the metabolite thiodiglycolic acid. Oral doses of 0.19, 1.125, and 2.25 g CMC in a second group of 12 healthy volunteers did not reveal dose dependence of the urinary excretion of the sulphoxides or of thiodiglycolic acid. Serum concentration-time-curves of CMC, (S)- and (R)-CMC sulphoxide were measured in a group of 9 healthy volunteers. The CMC sulphoxides in serum reached 1.5% of the parent substance after 4 hours. The ratio of CMC to its sulphoxide metabolites was similar in serum and urine. Pharmacogenetic polymorphism of sulphoxidation was not confirmed by the specific HPLC methods used.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265849
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  • 5
    Electronic Resource
    Electronic Resource
    Pharmacokinetic interaction between cyclosporin and diltiazem (1990)
    Springer
    European journal of clinical pharmacology 38 (1990), S. 237-242 
    Details
    ISSN: 1432-1041
    Keywords: cyclosporin A ; diltiazem ; pharmacokinetics ; kidney transplantation ; drug metabolism ; cytochrome P-450 ; drug interactions ; human liver microsomes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Previous reports have indicated that administration of the calcium antagonist diltiazem results in major changes in the pharmacokinetics of cyclosporin A (CyA). A new clinical trial was undertaken in 22 renal transplant patients receiving a constant dose of cyclosporin to further explore this interaction. Coadministration of diltiazem for one week produced an increase in the blood concentration of CyA and its metabolites 17 and 18 in almost all patients, but no increase in CyA metabolites 1 and 21. The mean whole blood CyA trough level determined by HPLC rose from 117 ng·ml−1 to 170 ng·ml−1 after one week on diltiazem, and the mean trough level of metabolite 17 rose similarly from 184 ng·ml−1 before to 336 ng·ml−1. Based on experiments with microsomes from human liver the effect of diltiazem was due to noncompetitve inhibition of CyA-metabolism by diltiazem, and the increased concentration of metabolite 17 might have been due to stronger inhibition of its secondary metabolism steps.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315023
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  • 6
    Electronic Resource
    Electronic Resource
    Separation of ribosomal protein-protein crosslinks fromBacillus stearothermophilus and ribosomal proteins from archaebacteria by high performance liquid chromatography (1986)
    Springer
    Chromatographia 22 (1986), S. 249-254 
    Details
    ISSN: 1612-1112
    Keywords: Column liquid chromatography ; Reversed phase operation ; Ribosomal proteins ; Methanococcus vannielii ; Bacillus stearothermophilus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary High performance liquid chromatography was used to separate proteins derived from ribosomes of the archaebacteriumMethanococcus vannielii. Several methods of separation were tested: size exclusion chromatography, reversed phase and ion-exchange chromatography. Best results were obtained using reversed phase columns and volatile buffers that allow direct sequence analysis of the proteins. In addition, HPLC was used to separate crosslinked protein-protein pairs fromBacillus stearothermophilus ribosomes on a preparative scale. Identification of crosslinked amino acids is a prerequisite for more detailed topographical investigations of this cell organelle. The purification of the 50S crosslink L23–L29 was achieved by a combination of two different reversed phase columns, and the 30S crosslink S13–S19 was purified after salt extraction by size exclusion chromatography. The methods described here allow a rapid preparation of ribosomal proteins for structural and functional investigations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02268768
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