Abstract
The metabolism of dipropyl disulfide (DPDS), anAllium sulfur compound, was investigated in rat liver cell subfractions and in an isolated perfused rat liver. DPDS is oxidized to dipropyl thiosulfinate (DPDSO) by rat microsomes. The contribution of cytochrome P450 enzymes (CYPs) or flavin-containing monooxygenases (FMO) to the formation of DPDSO from its precursor was investigated. In rat microsomes, the reaction followed Michaelis-Menten kinetics with aKm = 0.52 ± 0.1 mM and aVmax = 5.91 ± 0.5 nmol/min/mg of protein, respectively (mean ± S.E., n = 4). Both FMOs and CYPs were involved in DPDS oxidation, although the contribution of CYPs was predominant. Liver microsomes from phenobarbital-treated rats showed a 3.2-fold increase in the rate of formation of DPDSO. Among many CYP isoform-specific inhibitors, only CYP2B1/2 inhibitors decreased the formation of DPDSO and the best correlation between the rate of DPDS oxidation with specific monooxygenase activities was found with a marker of CYP2B1/2 activity. The action of phase II enzymes on DPDS metabolism was studied by incubating DPDS or DPDSO with liver cytosols or microsomes. Two metabolites were formed from DPDS: propylglutathione sulfide conjugate and propylmercaptan, whereas with DPDSO, only the glutathione conjugate was observed. No conjugate compound was detected in the presence of UDP-glucuronyl transferases. When isolated rat liver was perfused with DPDS, different metabolites were obtained in the output and in the liver tissues: propylmercaptan appeared in the output, whereas methylpropyl sulfide, methylpropyl sulfone, and propylglutathione sulfide were detected in the liver tissue.
Footnotes
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Send reprint requests to: Caroline Teyssier, Unitéde Toxicologie Nutritionnelle, Institut National de la Recherche Agronomique, 17 rue Sully, 21034 Dijon Cedex, France. E-mail:teyssier{at}dijon.inra.fr
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This work was supported by the Conseil Régional de Bourgogne.
- Abbreviations used are::
- DADS
- diallyl disulfide
- AM
- allyl mercaptan
- GC-MS
- gas chromatography-mass spectrometry
- CYP
- cytochrome P450
- DADSO
- allicin
- DPDS
- dipropyl disulfide
- DPDSO
- dipropyl thiosulfinate
- ECOD
- 7-ethoxycoumarin deethylase
- EROD
- ethoxyresorufin O-deethylase
- FMO
- flavin-containing monooxygenase
- FTIR
- Fourier transform infrared
- GSH
- reduced glutathione
- GST
- glutathioneS-transferase
- MMO
- methimazole oxidase
- MPS
- methylpropyl sulfide
- MPSO2
- methylpropyl sulfone
- PGS
- propylglutathione sulfide
- PM
- propyl mercaptan
- PNPH
- p-nitrophenol hydroxylase
- PROD
- pentoxyresorufin depentylase
- UDGPA
- uridine diphosphate glucuronic acid
- UGT
- UDP-glucuronyl transferase
- Received October 28, 1999.
- Accepted February 22, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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