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Drug metabolism and disposition: the biological fate of chemicals

Metabolism of dipropyl disulfide by rat liver phase I and phase II enzymes and by isolated perfused rat liver.


PMID 10820136

Abstract

The metabolism of dipropyl disulfide (DPDS), an Allium 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 a K(m) = 0.52 +/- 0.1 mM and a V(max) = 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.

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