Biomedical subjects
Publications and source records attributed to B Walker.
A 'ketomethylene' peptide, N-benzyloxycarbonyl-L-prolyl-L-alanyl-3-amino- 2-oxopropyl-L-leucyl-L-alanylglycine ethyl ester, was synthesized and shown to be a fairly potent competitive inhibitor of human skin collagenase.
Smokeless tobacco (snuff and chewing tobacco) is reemerging as a popular form of tobacco, particularly among male adolescents. In different regions of the United States, from 8 to 36 percent of male high-school students are regular users. The use of smokeless tobacco has been shown to cause oral-pharyngeal cancer. The strongest link is with cancers of the cheek and gum. White mucosal lesions (leukoplakia) are found in 18 to 64 percent of users, often at the site where the tobacco was held. Other associations have been suggested for cancers of the esophagus, larynx, and pancreas. Nitrosamines, found in high concentrations in smokeless tobacco, most likely have a role in its carcinogenicity. Other health problems include periodontal disease, acute elevations of blood pressure, and dependence. In early 1986, after action at the state level, Congress enacted a federal law requiring health-warning labels on packages of smokeless tobacco and a ban on electronic advertising. Other regulatory measures under consideration include raising state and federal excise taxes, tightening controls on advertising, and prohibiting sales to minors. In view of the recent growth of this problem, policy makers are taking the opportunity to intervene with preventive measures to protect a new generation of tobacco users.
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We assessed the anti-mutagenic and anti-promotion properties of two flavones, apigenin and robinetin, and of indole-3-carbinol, because these compounds have been reported in vegetables, the consumption of which has been associated with reduced rates of cancer. However, the active components of these foods and their effects on carcinogenesis have not been established. Anti-mutagenicity was determined in the Salmonella typhimurium assay by measuring the effects of the test compounds on bacterial mutagenesis induced by methyl-nitrosourea (MNU), methyl-n-nitro-N-nitrosoguanidine (MNNG), benzo[a]pyrene (BaP) or 2-aminoanthracene (2-AA). Inclusion of apigenin resulted in a 62% and a 43% inhibition of mutagenicity with 13 nmol of 2-AA and 30 nmol BaP respectively. Robinetin caused an 87% inhibition of mutagenicity by 2-AA, but indole-3-carbinol had little or no effect on the mutagenicity of any of the compounds. None of the three compounds inhibited mutagenesis by MNU or MNNG and none were mutagenic or toxic when tested in the absence of mutagenic compounds at doses up to 20 micrograms/plate. Anti-promotion properties were assessed by measuring the effects of apigenin, robinetin and indole-3-carbinol on induction of ornithine decarboxylase activity (ODC) in mouse epidermis by 17 nmol 12-O-tetradecanoyl phorbol-13-acetate (TPA). Pretreatment of the skin half an hour before TPA with apigenin, robinetin, butylated hydroxyanisole, 13-cis-retinoic acid (all at 50 mumol) or di-fluoromethylornithine (1.6 mumol) inhibited ODC induction at 6 h after TPA by 67-80%. Pretreatment with 50 mumol indole-3-carbinol caused a 78% elevation in the TPA induction at this time. Dose response measurements were conducted with apigenin, indole-3-carbinol and robinetin. Inhibition by 30-90% of TPA-induced ODC was observed at 6 h after TPA in mice pretreated with 12.5-100 mumol apigenin. Pretreatment with 37.5 or 50 mumol indole-3-carbinol or 0.5, 12.5 or 25 mumol robinetin resulted in elevated induction of epidermal ODC by TPA at 6 h after TPA. However, treatment with 50 or 100 mumol robinetin diminished ODC induction at 6 h after TPA. Treatment with 100 mumol apigenin or 50 or 100 mumol indole-3-carbinol in non-TPA-treated mouse skin caused elevations in epidermal ODC. In comparing the time course of ODC induction, indole-3-carbinol (50 mumol) pretreatment shifted the induction of epidermal ODC to earlier times, in addition to elevating ODC induction by TPA.(ABSTRACT TRUNCATED AT 400 WORDS)
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The fluoromethyl ketone derivatives of peptides are now available through several synthetic approaches and can be examined with respect to their properties as protease inhibitors. It had been expected that the fluoro atom might be too inert for nucleophilic displacement and that irreversible inactivation might not be achievable by this type of derivative in contrast to chloromethyl ketones. However, with serine and cysteinyl proteases, alkylation of the enzyme does take place although the rates are not similar to those of the chloromethyl ketones. Of the two classes, thiol proteases are more readily inactivated and the fluoromethyl ketones are almost as effective as the chloromethyl ketones. Our observations confirm and extend those of Rasnick (Anal. Biochem. 149, 461-465 (1985)). The structure of the peptidyl portion of the reagent controls specificity of inhibition in the typical manner of affinity-labels for proteases. However, fluoromethyl ketones are considerably less reactive to nucleophiles such as the thiol group of glutathione, than chloromethyl ketones and, therefore, this new class of inhibitors may provoke fewer side reactions when used in biological studies.
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The kinetics for the inactivation of thrombin (EC 3.4.21.5) by a series of peptides containing C-terminal arginyl chloromethane in the presence of substrate were determined. The inhibitor effectiveness was analysed so as to allow for both the evaluation of the affinity with which the enzyme binds the inhibitor before irreversible modification and also the rate of covalent-bond formation between enzyme and inhibitor. The results obtained show that the observed large range in inhibitor effectiveness can be accounted for almost entirely by marked differences in affinity, with only small variations in rates of formation of covalent complex.
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1-(N-Amino-n-hexyl)carbamoylimidazole hydrochloride was synthesized and shown to be a potent irreversible inhibitor of human urokinase (EC 3.4.21.31), pig kidney-cell plasminogen activator (EC 3.4.21.-), human plasmin (EC 3.4.21.7) and bovine pancreatic beta-trypsin (EC 3.4.21.4). The kinetics of inhibition of the enzymes were determined by monitoring the hydrolysis of an appropriate fluorogenic substrate. Bovine thrombin and Factor Xa are hardly affected by the inhibitor.
The behaviour of human urokinase and porcine kidney cell plasminogen activator towards some synthetic substrates has been investigated. Although N- benzyloxycarbonylglycylglycyl -L-arginine 4-methyl-7- coumarylamide (Z-Gly-Gly-Arg-Amc) (I), glutaryl-Gly-Arg-Amc (II) and Z-Gly-Gly-Arg-Val-OMe (III) were substrates, Boc-Gly-Gly-Arg-Val-Val-Gly-Gly-OEt (IV) and Z-Ala-Pro-Gly-Arg-Val-Val-Gly-Gly-OEt (V) were neither substrates nor inhibitors. Steady-state kinetic parameters for the hydrolysis of (II) and (III) by urokinase and porcine kidney cell plasminogen activator were similar.
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Relating current morbidity and mortality to environmental and occupational factors requires information on parameters of environmental exposure for practitioners of medicine and other health scientists. A fundamental source of that information is the exposure history recorded in hospitals, clinics, and other points of entry to the health care system. The qualitative and quantitative aspects of this issue are reviewed.
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To ascertain if the level of a left-to-right cardiac shunt can be reliably established by first-pass radionuclide angiocardiography with 99mTc-pertechnetate, 102 children have been studied; 19 without a shunt, 26 with an atrial septal defect (ASD), 45 with a ventricular septal defect (VSD), and 12 with a patent ductus arteriosus (PDA). Time-activity curves were generated over the right atrium and ventricle, and several quantitative parameters were derived from the curves. It was concluded that in the absence of right-sided valvular incompetence, the time-activity curves show the greatest abnormality in the cardiac chambers distal to the left-to-right shunt. The right ventricular curve is typically altered in ASD but cannot be relied upon to differentiate VSD or PDA. The identification of ASD is assisted by the use of two of the parameters, the count ratio C4:C1 and time ratio T2-T1.