Structure of the glutathione adduct of activated 3-methylindole indicates that an imine methide is the electrophilic intermediate.
Goat lung microsomes were incubated with glutathione (GSH) and 3-methylindole (3MI) to produce an adduct between GSH and an electrophilic metabolite of 3MI. The GSH-3MI adduct was purified by reverse-phase HPLC, and its structure elucidated by UV and NMR spectrometry and by thermospray LC/MS. The adduct was shown to be 3-[(glutathion-S-yl)-methyl]indole. Since nucleophilic GSH adds to the methyl position of 3MI without the incorporation of oxygen into the molecule, an epoxide metabolite is probably not the electrophilic intermediate. More likely, an imine methide intermediate, resulting from nitrogen oxidation and hydrogen abstraction from the methyl group by cytochrome P-450 monooxygenases, is the electrophilic intermediate. The imine methide electrophile is therefore proposed to be the toxic intermediate in 3MI-mediated pulmonary toxicity.
Nocerini
M R
MR
Yost
G S
GS
Carlson
J R
JR
Liberato
D J
DJ
Breeze
R G
RG
D000818:Animals; D001711:Biotransformation; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002853:Chromatography, Liquid; D005978:Glutathione / Q000378:metabolism*; D006041:Goats; D007097:Imines / Q000378:metabolism*; D066298:In Vitro Techniques; D007211:Indoles / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D012862:Skatole / Q000378:metabolism*; D013056:Spectrophotometry, Ultraviolet
D007097:Imines; D007211:Indoles; D012862:Skatole; D005978:Glutathione