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

Journal Article · Wed Mar 01 04:00:00 EST 2006 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2005.06.017· OSTI ID:20783438

Sanga, Madhu ^[1]; Younis, Islam R ^[1]; Tirumalai, Padma S ^[1]; Bland, Tina M ^[1]; Banaszewska, Monica ^[2]; Konat, Gregory W ^[2]; Tracy, Timothy S ^[3]; Gannett, Peter M ^[1]; Callery, Patrick S ^[1]

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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)

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.

• OSTI ID: 20783438
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 211; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ALCOHOLS
DEATH
ENZYME INHIBITORS
ENZYMES
EPOXIDES
GLUTATHIONE
LIVER
METABOLISM
MICROSOMES
PYROLYSIS
PYROLYSIS PRODUCTS
STYRENE
TOXICITY