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Biomedical subjects

T Wolff

Publications and source records attributed to T Wolff.

At least 109 records · Page 6Linked to original sources
PubMed1985

Substrate specificity of human liver cytochrome P-450 debrisoquine 4-hydroxylase probed using immunochemical inhibition and chemical modeling.

A significant population of humans (5 to 10%) are phenotypic poor metabolizers of debrisoquine. We have isolated the cytochrome P-450 isozyme from rat liver responsible for this activity and have shown that antibodies raised against the protein are able to inhibit this catalytic activity in human liver microsomes (Distlerath, L. M., and Guengerich, F. P., Proc. Natl. Acad. Sci. USA, 81: 7348-7352, 1984). These antibodies were utilized to determine which metabolic transformations are linked to debrisoquine 4-hydroxylation in human liver microsomes using techniques of immunochemical inhibition. The antibodies almost completely inhibited debrisoquine 4-hydroxylation and bufuralol 1'-hydroxylation in microsomes prepared from several different human livers. The oxidation of the pyrrolizidine alkaloids lasiocarpine and monocrotaline were inhibited by roughly one-third. The antibodies did not inhibit N,N-dimethylnitrosamine N-demethylation, oxidation of vinylidene chloride to 2,2-chloroacetaldehyde, oxidation of trichloroethylene to chloral, N-oxidation of azoprocarbazine, morphine N-demethylation, diazepam N-demethylation, oxidation of benzo(a)pyrene to alkali-soluble metabolites, oxidation of benzo(a)pyrene 7,8-dihydrodiol to products covalently bound to DNA, the N- and ring-oxidation of 1- and 2-naphthylamine and 2-aminofluorene, or the conversion of aflatoxin B1 to DNA adducts or aflatoxin Q1. Studies with space-filling models of the drugs the metabolism of which is associated with debrisoquine 4-hydroxylase in the literature indicated that all can be fitted to a general structure in which a basic nitrogen is about 5 A away from the site of carbon hydroxylation and a hydrophobic domain is near the site of hydroxylation. These results may be useful in predicting which chemicals may or may not be metabolized in an atypical manner by a segment of the human population.

Aflatoxin B1↗
PubMed1984

Formation of dichloroacetylene from trichloroethylene in the presence of alkaline material--possible cause of intoxication after abundant use of chloroethylene-containing solvents.

Inhabitants of a private home suffered from symptoms possibly due to dichloroacetylene intoxication. Subsequent anamnesis revealed that abundant amounts of trichloroethylene had been used to remove a wax coating from a concrete-lined stone floor. This prompted us to examine whether dichloroacetylene could have been formed. Incubation of two commercial samples of trichloroethylene with aqueous alkaline solutions between pH 11 and 13, with mortar and tile filling material resulted in the formation of dichloroacetylene. This finding suggests formation of dichloroacetylene, when trichloroethylene comes into contact with moderately alkaline material, such as moist concrete.

Acetylene↗
PubMed1984

Prophylaxis against pulmonary complications in patients undergoing gall-bladder surgery. A comparison between early mobilization, physiotherapy with and without bronchodilatation.

A random comparison of early mobilization and chest physiotherapy (mainly breathing exercises) with or without bronchodilatating inhalations for prophylaxis against pulmonary complications in patients undergoing elective gall-bladder surgery is presented. The operation was performed with a subcostal incision and peroperatively, intercostal nerve block was administered. Preoperative pulmonary status (dynamic volume spirometry, peak expiratory flow rate, arterial blood gas analysis) showed no differences between the groups, and postoperative blood gas analysis and pulmonary X-ray or evident clinical findings did also not show any differences between the groups. Thus early mobilization was as effective in our study as the other prophylactic treatments. In patients without pulmonary disease perhaps early mobilization and efficient analgesia after surgery is as effective as more resource demanding physiotherapy for prophylaxis against postoperative pulmonary complications.

Aged↗
PubMed1981

Age-, sex-, and strain-dependent differences in the induction of enzyme-altered islands in rat liver by diethylnitrosamine.

The formation of foci with loss of ATPase and emergence of gamma-GTase was studied histochemically in livers of male and female Wistar and Sprague-Dawley rats of 3--4 and 6--7 weeks of age, respectively, after application of diethylnitrosamine. A single dose of 8 mg/kg body weight induced a considerable island formation in weanlings of both sexes. Island induction in adults was observed only after repeated application. No difference in island size and number was observed with the exception of greater island size and Sprague-Dawley females. Sex-dependent differences in susceptibility to island induction were observed in weanlings, females being more sensitivity than males and Sprague-Dawley females being the most sensitive of all. No correlation was seen between monooxygenase activity and the extent of island formation. The coincidence of ATPase-deficiency and emergence of gamma-GTase was highest in Sprague-Dawley females. The importance of this result in respect to cancer formation is discussed. Weanling Sprague-Dawley females seemed to be the most suitable for use in a screening test system for chemical carcinogenicity, especially for testing low doses or weak carcinogens.

Adenosine Triphosphatases↗
PubMed1980

Involvement of phenolic metabolites in the irreversible protein-binding of 14C-bromobenzene catalysed by rat liver microsomes.

During microsomal metabolism of 14C-bromobenzene, radioactive material was irreversibly bound to microsomal protein. Although primary monooxygenation of aromatic hydrocarbons leads to the formation of reactive epoxides which may bind to protein, our results indicate that reactive intermediates formed via oxidation of the phenolic metabolites substantially contribute to the overall binding. This conclusion is supported by the following observations: 1) The binding of radioactivity continued to increase even though the primary metabolism was terminated; 2) Addition of UDP-glucuronic acid largely reduced the amount of the free phenols in the incubation mixture and simultaneously decreased the binding; and 3) Inhibition of the epoxide hydratase by 1,1,1-trichloro-2-propene oxide (TCPO) completely prevented the formation of the dihydrodiols, but did not significantly affect the binding. Thus, the results are in agreement with our previous observations on the binding of 14C-naphthalene and 14C-dichlorobiphenyl, and suggest that phenols generated from these aromatic hydrocarbons are further metabolized to protein-binding species.

Animals↗
PubMed1980

Mutagenicity testing with Salmonella microsome test.

This in vitro mutagenicity test system comprises five different strains of S. typhimurium as target cells with the rat liver S-9 fraction and appropriate co-factors for metabolic activation of the chemical tested. The bacterial tester strains detect both mutations induced by base pair substitutions and intercalation (frame shift mutations). Usually 10(8)--10(9) cells of an overnight culture or an exponentially growing culture are incubated for 2-3 days with a mixture of S-9, co-factors, soft agar and the chemical on histidine-deficient agar. The S-9 fraction is obtained from the livers of rats pretreated with 500 mg/kg chlorinated biphenyls (Clophen A-50, Aroclor 1254) to obtain high metabolic activity. For reproducibility it is essential to standardize metabolic activity and protein content of the S-9 and to use three different concentrations thereof in the test system. Since solvents inhibit metabolic activation of the chemicals they must not exceed 4% of the final 2.6 ml incubate. Several independent studies have shown that between 85 and 93% of chemical carcinogens are mutagens in the test. Regarding extrapolation to man one has to consider that the test is preferentially adapted for metabolic activation of the chemicals, whereas inactivation processes are absent or are less active than in vivo. Thus, the test provides qualitative rather than quantitative information on mutagenic effects of a chemical.

Animals↗
PubMed1980

Aldrin epoxidation catalyzed by purified rat-liver cytochromes P-450 and P-448. High selectivity for cytochrome P-450.

Aldrin epoxidation was studied in monooxygenase systems reconstituted from purified rat liver microsomal cytochrome P-450 or P-448, NADPH-cytochrome c reductase, dilauroylphosphatidylcholine and sodium cholate. Cytochrome P-450, purified from hepatic microsomes of phenobarbital-treated rats, exhibited a high rate of dieldrin formation. The low enzyme activity observed in the absence of the lipid and sodium cholate was increased threefold by addition of dilauroylphosphatidylcholine and was further stimulated twofold by addition of sodium cholate. The apparent Km for aldrin in the complete system was 7 +/- 2 microM. SKF 525-A, at a concentration of 250 microM, inhibited aldrin epoxidation by 65%, whereas 7,8-benzoflavone had no inhibitory effect at concentrations up to 250 microM. Addition of ethanol markedly increased epoxidase activity. The increase was threefold in the presence of 5% ethanol. When cytochrome P-448 purified from hepatic microsomes of 3-methylcholanthrene-treated rats was used, a very low rate of epoxidation was observed which was less than 3% of the activity mediated by cytochrome P-450 under similar assay conditions. Enzyme activity was independent of the lipid factor dilauroylphosphatidylcholine. The apparent Km for aldrin was 27 +/- 7 microM. The modifiers of monooxygenase reactions, 7,8-benzoflavone, SKF 525-A and ethanol, inhibited the activity mediated by cytochrome P-448. The I50 was 0.05, 0.2 and 800 mM, respectively. These results indicate that aldrin is a highly selective substrate for cytochrome P-450 species present in microsomes of phenobarbital-treated animals and is a poor substrate for cytochrome P-448. The two forms of aldrin epoxidase can be characterised by their turnover number, their apparent Km and their sensitivity to modifiers, like 7,8-benzoflavone and ethanol.

Aldrin↗
PubMed1979

Paresthesiae or no paresthesiae? Nerve lesions after axillary blocks.

Seeking paresthesiae when performing a peripheral nerve block may increase the risk of post-anesthetic neurological sequelae. To test this hypothesis, we prospectively followed two groups of patients who underwent hand surgery with an axillary block. In one group, the axillary plexus was located by actively seeking paresthesiae; in the other, pulsations of the axillary artery indicated an adequate position of the injection needle. Mepivacaine 10 mg/ml, with or without adrenaline, was used. The study included 533 patients, 290 in the paresthesia group and 243 in the artery group. Although unintentional, paresthesiae were elicited in 40% of patients in the artery group. Postanesthetic nerve lesions were seen in ten patients, eight in the paresthesia group and two in the artery group, all of whom had been blocked by mepivacaine with adrenaline. Symptoms varied between light paresthesiae lasting a few weeks, and severe paresthesiae, ache and paresis lasting more than 1 year. The etiology suspected was needle and perhaps injection trauma to the nerves during blocking. We conclude that whenever possible nerve blocks should be performed without searching for paresthesiae.

Adult↗
PubMed1978

Activation of [14C] chlorobiphenyls to protein-binding metabolites by rat liver microsomes.

The irreversible binding of [14C] 2,2'-di- and [14C] 2,4,5,2',4',5'-hexachlorobiphenyl ([14C] DCB and [14C] HCB) to protein was studied in the presence of rat liver microsomes and a NADPH-generating system. Protein-bound radioactivity was found with [14C] DCB but not with [14C] HCB. The binding of 14C-metabolites was increased by pretreatment of the rats with phenobarbital or polychlorinated biphenyls. Protein binding was linear for 80 min. In contrast, monohydroxy-metabolites of DCB were formed and degraded within 40 min. Inhibition of secondary oxidation of DCB by scavenging superoxide anions or by glucuronidation of the monophenols markedly decreased the protein binding. Addition of trichloropropene oxide or styrene oxide, both inhibitors of epoxide hydrase, did not significantly stimulate the binding. The results suggest that the majority of reactive metabolites of DCB arise from secondary metabolism, i.e., the subsequent oxidation of the phenolic metabolites. Arene oxides, the primary products, appear to play a minor role in the protein binding of DCB.

Albumins↗
PubMed1978

Somatosensory evoked potentials during Harrington instrumentation for scoliosis.

The somatosensory evoked potential can be obtained in the anesthetized patient during corrective surgery on the spine. The techniques of anesthesia and somatosensory evoked potential recordings described herein were utilized in fifty-five patients during surgical correction of scoliosis with Harrington instrumentation and spine fusion. No detectable complications were encountered and no neurological morbidity ensued in our series. This method may prove to be of significant value when potential injury to the spinal cord may be encountered during correction of spinal deformities.

Evoked Potentials↗