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Title: Epoxidation of the methamphetamine pyrolysis product, trans-phenylpropene, to trans-phenylpropylene oxide by CYP enzymes and stereoselective glutathione adduct formation

Abstract

Pyrolytic products of smoked methamphetamine hydrochloride are well established. Among the various degradation products formed, trans-phenylpropene (trans-{beta}-methylstyrene) is structurally similar to styrene analogues known to be bioactivated by CYP enzymes. In human liver microsomes, trans-phenylpropene was converted to the epoxide trans-phenylpropylene oxide (trans-2-methyl-3-phenyloxirane) and cinnamyl alcohol. Incubation of trans-phenylpropene with microsomes in the presence of enzyme-specific P450 enzyme inhibitors indicated the involvement of CYP2E1, CYP1A2, and CYP3A4 enzymes. Both (R,R)-phenylpropylene oxide and (S,S)-phenylpropylene oxide were formed in human liver microsomal preparations. Enantiomers of trans-phenylpropylene oxide were stereoselectively and regioselectively conjugated in a Phase II drug metabolism reaction catalyzed by human liver cytosolic enzymes consisting of conjugation with glutathione. The structure of the phenylpropylene oxide-glutathione adduct is consistent with nucleophilic ring-opening by attack at the benzylic carbon. Exposure of cultured C6 glial cells to (S,S)-phenylpropylene oxide produced a cytotoxic response in a concentration-dependent manner based on cell degeneration and death.

Authors:
 [1];  [1];  [1];  [1];  [2];  [2];  [3];  [1];  [4]
  1. Department of Basic Pharmaceutical Sciences, West Virginia University, 1 Medical Center Drive, Morgantown, WV 26506 (United States)
  2. Department of Neurobiology and Anatomy, West Virginia University, Morgantown, WV 26506 (United States)
  3. Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN 55455 (United States)
  4. Department of Basic Pharmaceutical Sciences, West Virginia University, 1 Medical Center Drive, Morgantown, WV 26506 (United States). E-mail: pcallery@hsc.wvu.edu
Publication Date:
OSTI Identifier:
20783438
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 211; Journal Issue: 2; Other Information: DOI: 10.1016/j.taap.2005.06.017; PII: S0041-008X(05)00382-0; Copyright (c) 2005 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; ALCOHOLS; DEATH; ENZYME INHIBITORS; ENZYMES; EPOXIDES; GLUTATHIONE; LIVER; METABOLISM; MICROSOMES; PYROLYSIS; PYROLYSIS PRODUCTS; STYRENE; TOXICITY

Citation Formats

Sanga, Madhu, Younis, Islam R., Tirumalai, Padma S., Bland, Tina M., Banaszewska, Monica, Konat, Gregory W., Tracy, Timothy S., Gannett, Peter M., and Callery, Patrick S. Epoxidation of the methamphetamine pyrolysis product, trans-phenylpropene, to trans-phenylpropylene oxide by CYP enzymes and stereoselective glutathione adduct formation. United States: N. p., 2006. Web. doi:10.1016/j.taap.2005.06.017.
Sanga, Madhu, Younis, Islam R., Tirumalai, Padma S., Bland, Tina M., Banaszewska, Monica, Konat, Gregory W., Tracy, Timothy S., Gannett, Peter M., & Callery, Patrick S. Epoxidation of the methamphetamine pyrolysis product, trans-phenylpropene, to trans-phenylpropylene oxide by CYP enzymes and stereoselective glutathione adduct formation. United States. doi:10.1016/j.taap.2005.06.017.
Sanga, Madhu, Younis, Islam R., Tirumalai, Padma S., Bland, Tina M., Banaszewska, Monica, Konat, Gregory W., Tracy, Timothy S., Gannett, Peter M., and Callery, Patrick S. Wed . "Epoxidation of the methamphetamine pyrolysis product, trans-phenylpropene, to trans-phenylpropylene oxide by CYP enzymes and stereoselective glutathione adduct formation". United States. doi:10.1016/j.taap.2005.06.017.
@article{osti_20783438,
title = {Epoxidation of the methamphetamine pyrolysis product, trans-phenylpropene, to trans-phenylpropylene oxide by CYP enzymes and stereoselective glutathione adduct formation},
author = {Sanga, Madhu and Younis, Islam R. and Tirumalai, Padma S. and Bland, Tina M. and Banaszewska, Monica and Konat, Gregory W. and Tracy, Timothy S. and Gannett, Peter M. and Callery, Patrick S.},
abstractNote = {Pyrolytic products of smoked methamphetamine hydrochloride are well established. Among the various degradation products formed, trans-phenylpropene (trans-{beta}-methylstyrene) is structurally similar to styrene analogues known to be bioactivated by CYP enzymes. In human liver microsomes, trans-phenylpropene was converted to the epoxide trans-phenylpropylene oxide (trans-2-methyl-3-phenyloxirane) and cinnamyl alcohol. Incubation of trans-phenylpropene with microsomes in the presence of enzyme-specific P450 enzyme inhibitors indicated the involvement of CYP2E1, CYP1A2, and CYP3A4 enzymes. Both (R,R)-phenylpropylene oxide and (S,S)-phenylpropylene oxide were formed in human liver microsomal preparations. Enantiomers of trans-phenylpropylene oxide were stereoselectively and regioselectively conjugated in a Phase II drug metabolism reaction catalyzed by human liver cytosolic enzymes consisting of conjugation with glutathione. The structure of the phenylpropylene oxide-glutathione adduct is consistent with nucleophilic ring-opening by attack at the benzylic carbon. Exposure of cultured C6 glial cells to (S,S)-phenylpropylene oxide produced a cytotoxic response in a concentration-dependent manner based on cell degeneration and death.},
doi = {10.1016/j.taap.2005.06.017},
journal = {Toxicology and Applied Pharmacology},
number = 2,
volume = 211,
place = {United States},
year = {Wed Mar 01 00:00:00 EST 2006},
month = {Wed Mar 01 00:00:00 EST 2006}
}
  • The metabolism of the environmental carcinogen fluoroanthene by human liver microsomes was compared to that by liver microsomes from rats treated with Aroclor 1254. Although the human-derived system gave primarily one product, similar metabolites were noted from each system. Enantiomers of the major metabolic product, in both cases the trans-2,3-dihydrodiol, were separated by chiral stationary-phase chromatography. Absolute configurations were assigned by application of the benzoate exciton chirality rules to the CD spectra of the 4-(dimethylamino)benzoyl esters. Liver microsomes from Aroclor 1254-treated rats produced the R,R enantiomer of the diol in 75-78% enantiomeric excess, while human liver microsomes produced this enantiomermore » in only 6-12% excess. The activities of these enantiomers were compared in Salmonella typhimurium strain TM677 mutagenicity assays employing the 9000g supernatant of Aroclor 1254-induced rat liver homogenates. Both the syn- and anti-2,3-dihydrodiol 1,10b-epoxides, which had only been inferred to be metabolites in previous studies, were isolated from the microsomal incubations by preparative reverse-phase HPLC. The evident exceptional aqueous stabilities of these diol epoxides were further examined by half-life determination experiments. Their tetrahydrotetrol hydrolysis products were also noted in the metabolite HPLC profiles. The structures of the tetrahydrotetrols were confirmed by total synthesis.« less
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