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.affiliation: Department of Basic Pharmaceutical Sciences, West Virginia University, 1 Medical Center Drive, Morgantown, WV 26506, USA.
authors.forename: Madhu
authors.initials: M
authors.lastname: Sanga
authors.forename: Islam R
authors.initials: IR
authors.lastname: Younis
authors.forename: Padma S
authors.initials: PS
authors.lastname: Tirumalai
authors.forename: Tina M
authors.initials: TM
authors.lastname: Bland
authors.forename: Monica
authors.initials: M
authors.lastname: Banaszewska
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Konat
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Tracy
authors.forename: Peter M
authors.initials: PM
authors.lastname: Gannett
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Callery
mesh_terms: D000475:Alkenes / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D045744:Cell Line, Tumor; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002853:Chromatography, Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004852:Epoxy Compounds / Q000378:metabolism*; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D013058:Mass Spectrometry; D008694:Methamphetamine / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D015394:Molecular Structure; D010084:Oxidation-Reduction / Q000187:drug effects; D020005:Propanols / Q000378:metabolism; D013237:Stereoisomerism; D013343:Styrenes / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D013997:Time Factors
chemical_list: D000475:Alkenes; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D007527:Isoenzymes; D020005:Propanols; D013343:Styrenes; C509597:phenylpropylene oxide; D008694:Methamphetamine; D003577:Cytochrome P-450 Enzyme System; C505958:1-phenylpropene; D005978:Glutathione; C020722:cinnamyl alcohol