Note:

No description available.

published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy

Organic cations (OC's) are actively secreted by the renal proximal tubules in a number of species. The transepithelial transport of OC's involves a secondary active OC/H+ exchange process at the brush border (luminal) membrane. This study employed rabbit renal brush border membrane vesicles (BBMV) to investigate the structural requirements associated with substrate recognition at the OC transporter. A number of compounds (an N-alkylammonium series, an N1-alkylpyridinium series and some clinically important organic bases) were tested for their ability to competitively block the uptake of radioactively labelled tetraethylammonium (TEA) into BBMV. The inhibitory effectiveness of these compounds was correlated to the degree of hydrophobicity surrounding the positively-charged nitrogenous nucleus common to all the inhibitors. Preloading BBMV with N1-substituted pyridines trans-stimulated the uptake of TEA, suggesting that these compounds are translocated substrates for the OC transporter. The activity of the OC transport inhibitor and neurotoxin 1-methyl-4-phenylpyridinium was of special interest, and thus its transport characteristics were fully evaluated.

Thesis (Ph. D.)--University of Hong Kong, 1996. / Includes bibliographical references (leaf 180-212).

No description available.

No description available.

Haloalkenes were shown to react with cysteine, N-acetyl cysteine, or glutathione to form halogenated vinylthio (HVT) or saturated conjugates. When HVT were administered iv to rabbits, active transport in the renal tubules was inhibited 50% at doses as low as 20 mg/kg within 1 hr after dosing. There was sloughing of the renal brush border membrane with the injury progressing to a specific renal tubular necrosis of the S₃ segment. In vitro studies with renal tubules found that the HVT produced a dose-response related inhibition of acid/base transport, with complete inhibition of transport occurring at 1 mM. The cysteine conjugate synthesized from trichloroethylene, DCVC, inhibited tubular active transport 60 min after in vivo dosing (20-100 mg/kg), 45 min after exposure in the isolated perfused kidney (0.01-1 mM) and 15 min after incubation with isolated tubules (0.01-1 mM). All HVT conjugates had a similar potency with regard to transport inhibition in isolated tubules, with complete inhibition occurring at 1 mM within 15 min for cysteine conjugates compared to 45-60 min for the N-acetyl cysteine or glutathione conjugates. These latter conjugates are thought to be bioactivated to the cysteine conjugate prior to transport inhibition. Inhibition of tubular (gamma)-glutamyl transpeptidase by 1 mM AT-125 or 20 mM serine/borate prevented the inhibition of acid/base transport by the glutathione conjugate. In addition, the sequential formation of glutamate, glycine and the vinyl cysteine conjugate after tubule incubation with the glutathione conjugate provides further evidence for this bioactivation. The cysteine conjugates are thought to be further metabolized in tubules to a toxic intermediate by a brush border localized enzyme, C-S lyase. The inhibitor effect of this intermediate on acid/base transport is reversed in the presence of, or subsequent addition of, 6 mM exogenous glutathione. These studies provide further evidence for the nephrotoxicity of HVT, and formation of the nephrotoxic cysteine conjugates from glutathione and cysteine conjugates. The formation of saturated conjugates from CTFE was also demonstrated. These saturated and/or unsaturated conjugates may be responsible for haloalkene-induced nephrotoxicity.

No description available.

Thesis (Ph.D.)--University of Alberta, 2009. / A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Doctor of Philosophy, Oncology. Title from pdf file main screen (viewed on August 1, 2009). Includes bibliographical references.