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

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Abstract
We tested the hypothesis that an epoxide formed from diallyl sulfone (DASO 2 ) is responsible for inactivation of CYP2E1 in mu- rine and human lungs. An epoxide (1,2-epoxypropyl-3,3 9 -sul- fonyl-1 9 -propene (DASO 3 )) was synthesized from DASO 2 and conjugated with glutathione (GSH) to produce the conjugates S-(1 R,S -((1-hydroxymethyl-2,3 9 -sulfonyl)-1 9 -propenyl)ethyl)glu- tathione (diastereomers) and S-(1-((2 R,S -hydroxypropyl)-3,3 9 - sulfonyl)-1 9 -propenyl)glutathione (diastereomers). Analysis of these conjugates by high performance liquid chromatogra- phy revealed a major peak eluting at 20.5 min. This peak was detected in incubations of murine and human lung mi- crosomes containing DASO 2 and nicotinamide adenine dinu- cleotide phosphate (NADPH), and was not detected in incuba- tions performed in the absence of DASO 2 or NADPH. The amounts of epoxide-derived GSH conjugates formed in the in- cubations were concentration-dependent and achieved satu- ration at 0.75 mM DASO 2 . Formation of the conjugates was also time-dependent and peaked at 2.0 h after DASO 2 . The peak containing the GSH conjugates was also detected in in- cubations of CYP2E1-expressed lymphoblastoid microsomes, NADPH, and DASO 2 . Maximal amounts of DASO 3 , as esti- mated by formation of a 4-( p -nitrobenzyl)pyridine derivatized product, were detected in murine lung microsomes incubated for 35 min with 1 mM DASO 2 . The derivatized DASO 3 was not detectable in incubations of human lung microsomes. p -Nitro- phenol hydroxylation, a catalytic activity associated with CYP2E1, was reduced in murine and human lung microsomes incubated with DASO 2 , with decreases that were concentra- tion-dependent. Dose-dependent decreases in hydroxylase activity were also found in microsomes from mice treated in vivo with DASO 2 (25 to 200 mg/kg). These results supported the premise that an epoxide formed from DASO 2 mediates in- activation of lung CYP2E1. Furthermore, the findings sug- gested that the mouse model is relevant for studies of DASO 2 in human lung.