Epoxide Formation from Diallyl Sulfone Is Associated with CYP2E1 Inactivation in Murine and Human Lungs

We tested the hypothesis that an epoxide formed from diallyl sulfone (DASO2) is responsible for inactivation of CYP2E1 in murine and human lungs. An epoxide (1,2-epoxypropyl-3,3 ′ -sulfonyl-1 ′ -propene [DASO3]) was synthesized from DASO2 and conjugated with glutathione (GSH) to produce the conjugates S-(1R,S-[[1-hydroxymethyl-2,3 ′ -sulfonyl]-1 ′ -propenyl]ethyl)glutathione (diastereomers) and S-(1-[[2R,S-hydroxypropyl]-3,3 ′ -sulfonyl]-1 ′ -propenyl)glutathione (diastereomers). Analysis of these conjugates by high performance liquid chromatography revealed a major peak eluting at 20.5 min. This peak was detected in incubations of murine and human lung microsomes containing DASO2 and nicotinamide adenine dinucleotide phosphate (NADPH), and was not detected in incubations performed in the absence of DASO2 or NADPH. The amounts of epoxide-derived GSH conjugates formed in the incubations were concentration-dependent and achieved saturation at 0.75 mM DASO2. Formation of the conjugates was also time-dependen...