Am. J. Respir. Cell Mol. Biol., Volume 23, Number 5, November, 2000 687-695

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

Poh-Gek Forkert, Peter D. Premdas, and Raymond J. Bowers

Departments of Anatomy and Cell Biology and Chemistry, Queen's University, Kingston, Ontario, Canada

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-dependent and peaked at 2.0 h after DASO₂. The peak containing the GSH conjugates was also detected in incubations of CYP2E1-expressed lymphoblastoid microsomes, NADPH, and DASO₂. Maximal amounts of DASO₃, as estimated by formation of a 4-(p-nitrobenzyl)pyridine derivatized product, were detected in murine lung microsomes incubated for 35 min with 1 mM DASO₂. The derivatized DASO₃ was not detectable in incubations of human lung microsomes. p-Nitrophenol hydroxylation, a catalytic activity associated with CYP2E1, was reduced in murine and human lung microsomes incubated with DASO₂, with decreases that were concentration-dependent. Dose-dependent decreases in hydroxylase activity were also found in microsomes from mice treated in vivo with DASO₂ (25 to 200 mg/kg). These results supported the premise that an epoxide formed from DASO₂ mediates inactivation of lung CYP2E1. Furthermore, the findings suggested that the mouse model is relevant for studies of DASO₂ in human lung.

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