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Title: Cigarette smoke toxicants as substrates and inhibitors for human cytosolic SULTs

Abstract

The current study was designed to examine the role of sulfation in the metabolism of cigarette smoke toxicants and clarify whether these toxicants, by serving as substrates for the cytosolic sulfotransferases (SULTs), may interfere with the sulfation of key endogenous compounds. By metabolic labeling, [{sup 35}S]sulfated species were found to be generated and released into the media of HepG2 human hepatoma cells and primary human lung endothelial cells labeled with [{sup 35}S]sulfate in the presence of cigarette smoke extract (CSE). Concomitantly, several [{sup 35}S]sulfated metabolites observed in the medium in the absence of CSE either decreased or disappeared. Eleven previously prepared human cytosolic SULTs were tested for sulfating activity with CSE and known cigarette smoke toxicants as substrates. Activity data revealed SULT1A1, SULT1A2, SULT1A3, and SULT1C2 as major enzymes responsible for their sulfation. To examine their inhibitory effects on the sulfation of 17{beta}-estradiol by SULT1A1, enzymatic assays were performed in the presence of three representative toxicant compounds, namely N-hydroxy-4-aminobiphenyl (N-OH-4-ABP), 4-aminobiphenyl (4-ABP) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). IC{sub 50} values determined for the sulfation of 17{beta}-estradiol by SULT1A1 were 11.8 {mu}M, 28.2 {mu}M, and 500 {mu}M, respectively, for N-OH-4-ABP, 4-ABP and PhIP. Kinetic analyses indicated that the mechanism underlying the inhibition ofmore » 17{beta}-estradiol sulfation by these cigarette smoke toxicants is of a mixed competitive-noncompetitive type. Metabolic labeling experiments clearly showed inhibition of the production of [{sup 35}S]sulfated 17{beta}-estradiol by N-OH-4-ABP in a concentration-dependent manner in HepG2 cells. Taken together, these results suggest that sulfation plays a significant role in the metabolism of cigarette smoke compounds. By serving as substrates for SULTs, cigarette smoke toxicants may interfere with the metabolism of 17{beta}-estradiol and other endogenous compounds.« less

Authors:
 [1];  [1];  [1];  [2];  [3];  [4]
  1. Biomedical Research Center, University of Texas Health Center, 11937 U.S. Highway 271, Tyler, TX 75708 (United States)
  2. Division of Arts and Sciences, Jarvis Christian College, Hawkins, TX 75765 (United States)
  3. School of Mathematics and Science, J. Sargeant Reynolds Community College, Richmond, VA 23285 (United States)
  4. Biomedical Research Center, University of Texas Health Center, 11937 U.S. Highway 271, Tyler, TX 75708 (United States). E-mail: ming.liu@uthct.edu
Publication Date:
OSTI Identifier:
20976930
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 221; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2007.02.013; PII: S0041-008X(07)00085-3; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ENZYMES; ESTRADIOL; HEPATOMAS; HUMAN POPULATIONS; INHIBITION; LABELLING; LUNGS; METABOLISM; METABOLITES; PYRIDINE; SUBSTRATES; SULFATES; SULFATION; TOBACCO SMOKES

Citation Formats

Yasuda, Shin, Idell, Steven, Fu Jian, Carter, Glendora, Snow, Rhodora, and Liu, M.-C.. Cigarette smoke toxicants as substrates and inhibitors for human cytosolic SULTs. United States: N. p., 2007. Web. doi:10.1016/j.taap.2007.02.013.
Yasuda, Shin, Idell, Steven, Fu Jian, Carter, Glendora, Snow, Rhodora, & Liu, M.-C.. Cigarette smoke toxicants as substrates and inhibitors for human cytosolic SULTs. United States. doi:10.1016/j.taap.2007.02.013.
Yasuda, Shin, Idell, Steven, Fu Jian, Carter, Glendora, Snow, Rhodora, and Liu, M.-C.. Tue . "Cigarette smoke toxicants as substrates and inhibitors for human cytosolic SULTs". United States. doi:10.1016/j.taap.2007.02.013.
@article{osti_20976930,
title = {Cigarette smoke toxicants as substrates and inhibitors for human cytosolic SULTs},
author = {Yasuda, Shin and Idell, Steven and Fu Jian and Carter, Glendora and Snow, Rhodora and Liu, M.-C.},
abstractNote = {The current study was designed to examine the role of sulfation in the metabolism of cigarette smoke toxicants and clarify whether these toxicants, by serving as substrates for the cytosolic sulfotransferases (SULTs), may interfere with the sulfation of key endogenous compounds. By metabolic labeling, [{sup 35}S]sulfated species were found to be generated and released into the media of HepG2 human hepatoma cells and primary human lung endothelial cells labeled with [{sup 35}S]sulfate in the presence of cigarette smoke extract (CSE). Concomitantly, several [{sup 35}S]sulfated metabolites observed in the medium in the absence of CSE either decreased or disappeared. Eleven previously prepared human cytosolic SULTs were tested for sulfating activity with CSE and known cigarette smoke toxicants as substrates. Activity data revealed SULT1A1, SULT1A2, SULT1A3, and SULT1C2 as major enzymes responsible for their sulfation. To examine their inhibitory effects on the sulfation of 17{beta}-estradiol by SULT1A1, enzymatic assays were performed in the presence of three representative toxicant compounds, namely N-hydroxy-4-aminobiphenyl (N-OH-4-ABP), 4-aminobiphenyl (4-ABP) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). IC{sub 50} values determined for the sulfation of 17{beta}-estradiol by SULT1A1 were 11.8 {mu}M, 28.2 {mu}M, and 500 {mu}M, respectively, for N-OH-4-ABP, 4-ABP and PhIP. Kinetic analyses indicated that the mechanism underlying the inhibition of 17{beta}-estradiol sulfation by these cigarette smoke toxicants is of a mixed competitive-noncompetitive type. Metabolic labeling experiments clearly showed inhibition of the production of [{sup 35}S]sulfated 17{beta}-estradiol by N-OH-4-ABP in a concentration-dependent manner in HepG2 cells. Taken together, these results suggest that sulfation plays a significant role in the metabolism of cigarette smoke compounds. By serving as substrates for SULTs, cigarette smoke toxicants may interfere with the metabolism of 17{beta}-estradiol and other endogenous compounds.},
doi = {10.1016/j.taap.2007.02.013},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 221,
place = {United States},
year = {Tue May 15 00:00:00 EDT 2007},
month = {Tue May 15 00:00:00 EDT 2007}
}
  • New modifications on the C-8 4-aminobenzyl unit of the previously reported 3-alkyl-1,8-dibenzylxanthine inhibitors of cPEPCK are presented. The most active compound reported here is the 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acid amide derivative 2 with an IC{sub 50} of 0.29 {+-} 0.08 {mu}M. An X-ray analysis of a heteroaromatic sulfonamide is presented showing a new {pi}-{pi} interaction.
  • Alpha-1-proteinase inhibitors (alpha 1PI) containing methionine (Met-358) or valine (Met----Val-358) at the reactive center were synthesized in and purified to homogeneity from recombinant yeast. The pure proteins were exposed to 1 of 4 different oxidizing systems: N-chlorosuccinimide (chemical oxidation), myeloperoxidase plus peroxide and halide (enzymatic oxidation), activated neutrophils (cellular oxidation), or gas-phase cigarette smoke. The effect of these treatments on the leukocyte elastase inhibitory function of both proteins was then assessed. After brief exposures, substantial inactivation of the normal inhibitor occurred, whereas the mutant inhibitor remained fully active. More prolonged exposures led to complete inactivation of the normal protein andmore » partial inactivation of the mutant inhibitor. These results suggest that the reactive center methionyl residue in alpha 1PI is more rapidly affected by oxidants than are other oxidizable residues in the inhibitor; however, Met-358 is not the only residue in alpha 1PI whose modification can lead to the inactivation of the elastase inhibitory capacity of this protein.« less
  • Investigation of the effect of cigarette smoke on the serum trypsin inhibitory capacity (TIC) and antitrypsin content in 89 smokers compared with 37 nonsmokers revealed that cigarette smoking is associated with a significantly lower level of TIC. No alteration in serum antitrypsin content was found because of cigarette smoking. Further analysis of the data indicated a correlation between the magnitude of smoking and the reduction in serum TIC. The reduction of TIC in cigarette smokers is consistent with the recent findings of decreased alpha 1-antitrypsin activity in rat lung and the reduced elastase inhibitory capacity per mg of alpha 1-antitrypsinmore » found in the serum of smokers. The decrease in TIC in the serum of smokers, in addition to the reported decrease in elastolytic activity, may be useful in explaining the pathogenesis of emphysema frequently found in smokers.« less
  • Measurement of deposition of sidestream cigarette smoke in the human respiratory tract is important for assessing the health effects of sidestream cigarette smoke. We measured the deposition fraction of sidestream cigarette smoke in 5 normal adult male volunteers using sidestream smoke at a concentration similar to that encountered indoors with smokers present. The mean deposition was 11%. These data indicate that the deposition fraction of sidestream smoke is similar to other previously studied aerosols in the same size range and is much less than mainstream smoke.