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Metabolism of the chemoprotective agent diallyl sulfide to glutathione conjugates in rats.
Chem Res Toxicol. 1997 Mar; 10(3):318-27.CR

Abstract

The chemoprotective effects of diallyl sulfide (DAS), a flavor component of garlic, have been attributed to its inhibitory effects on CYP2E1-mediated bioactivation of certain carcinogenic chemicals. In addition to being a competitive inhibitor of CYP2E1 in vitro, DAS is known to cause irreversible inhibition of CYP2E1 in rats in vivo. The latter property is believed to be mediated by the DAS metabolite diallyl sulfone (DASO2), which is thought to be a mechanism-based inhibitor of CYP2E1, although the underlying mechanism remains unknown. In order to investigate the nature of the reactive intermediate(s) responsible for the inactivation of CYP2E1 by DAS and its immediate metabolites, the present studies were carried out to detect and identify potential glutathione (GSH) conjugates of DAS and its metabolites diallyl sulfoxide (DASO) and DASO2. By means of ionspray LC-MS/MS, ten GSH conjugates were identified in bile collected from rats dosed with DAS, namely: S-[3-(S'-allyl-S'-dioxomercapto)-2-hydroxypropyl]glutathione (M1, M2; diastereomers), S-[3-(S'-allyl-S'-dioxomercapto)-2-hydroxypropyl]-glutathione (M5), S-[2-(S'-allyl-S'-dioxomercapto)-1-(hydroxymethyl)ethyl]glutathion e (M3, M4; diastereomers), S-[3-(S'-allylmercapto)-2-hydroxypropyl]glutathione (M6), S-(3-hydroxypropyl)-glutathione (M7), S-(2-carboxyethyl)glutathione (M8), allyl glutathionyl disulfide (M9), and S-allylglutathione (M10). With the exception of M6, all of the above GSH conjugates were detected in the bile of rats treated with DASO, while only M3, M4, M5, M7, M8, and M10 were found in the bile of rats treated with DASO2. Experiments conducted in vitro showed that GSH reacted spontaneously with DASO to form conjugates M9 and M10, and with DASO2 to form M10. In the presence of NADPH and GSH, incubation of DAS with cDNA-expressed rat CYP2E1 resulted in the formation of metabolites M6, M9, and M10, while incubation with DASO led to the formation of M3, M4, M5, M9, and M10. When DASO2 acted as substrate, CYP2E1 generated only conjugates M3, M4, M5, and M10. These results indicate that while DAS and DASO undergo extensive oxidation in vivo at the sulfur atom, the allylic carbon, and the terminal double bonds, CYP2E1 preferentially catalyzes oxidation of the sulfur atom to form the sulfoxide and the sulfone (DASO and DASO2). However, it appears that the end product of this sequence, namely, DASO2, undergoes further CYP2E1-mediated activation of the olefinic pi-bond, a reaction which transforms many terminal olefins to potent mechanism-based P450 inhibitors. We hypothesize, therefore, that it is this final metabolic event with DASO2 which leads to autocatalytic destruction of CYP2E1 and which is mainly responsible for the chemoprotective effects of DAS in vivo.

Authors+Show Affiliations

Jin L
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195, USA.
Baillie TA
No affiliation info available

MeSH

Allyl CompoundsAnimalsAntioxidantsBileCells, CulturedChromatography, LiquidCytochrome P-450 CYP2E1Cytochrome P-450 CYP2E1 InhibitorsGas Chromatography-Mass SpectrometryGlutathioneMagnetic Resonance SpectroscopyMaleRatsRats, Sprague-DawleySulfides

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

9084912

Citation

Jin, L, and T A. Baillie. "Metabolism of the Chemoprotective Agent Diallyl Sulfide to Glutathione Conjugates in Rats." Chemical Research in Toxicology, vol. 10, no. 3, 1997, pp. 318-27.
Jin L, Baillie TA. Metabolism of the chemoprotective agent diallyl sulfide to glutathione conjugates in rats. Chem Res Toxicol. 1997;10(3):318-27.
Jin, L., & Baillie, T. A. (1997). Metabolism of the chemoprotective agent diallyl sulfide to glutathione conjugates in rats. Chemical Research in Toxicology, 10(3), 318-27.
Jin L, Baillie TA. Metabolism of the Chemoprotective Agent Diallyl Sulfide to Glutathione Conjugates in Rats. Chem Res Toxicol. 1997;10(3):318-27. PubMed PMID: 9084912.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Metabolism of the chemoprotective agent diallyl sulfide to glutathione conjugates in rats. AU - Jin,L, AU - Baillie,T A, PY - 1997/3/1/pubmed PY - 1997/3/1/medline PY - 1997/3/1/entrez SP - 318 EP - 27 JF - Chemical research in toxicology JO - Chem Res Toxicol VL - 10 IS - 3 N2 - The chemoprotective effects of diallyl sulfide (DAS), a flavor component of garlic, have been attributed to its inhibitory effects on CYP2E1-mediated bioactivation of certain carcinogenic chemicals. In addition to being a competitive inhibitor of CYP2E1 in vitro, DAS is known to cause irreversible inhibition of CYP2E1 in rats in vivo. The latter property is believed to be mediated by the DAS metabolite diallyl sulfone (DASO2), which is thought to be a mechanism-based inhibitor of CYP2E1, although the underlying mechanism remains unknown. In order to investigate the nature of the reactive intermediate(s) responsible for the inactivation of CYP2E1 by DAS and its immediate metabolites, the present studies were carried out to detect and identify potential glutathione (GSH) conjugates of DAS and its metabolites diallyl sulfoxide (DASO) and DASO2. By means of ionspray LC-MS/MS, ten GSH conjugates were identified in bile collected from rats dosed with DAS, namely: S-[3-(S'-allyl-S'-dioxomercapto)-2-hydroxypropyl]glutathione (M1, M2; diastereomers), S-[3-(S'-allyl-S'-dioxomercapto)-2-hydroxypropyl]-glutathione (M5), S-[2-(S'-allyl-S'-dioxomercapto)-1-(hydroxymethyl)ethyl]glutathion e (M3, M4; diastereomers), S-[3-(S'-allylmercapto)-2-hydroxypropyl]glutathione (M6), S-(3-hydroxypropyl)-glutathione (M7), S-(2-carboxyethyl)glutathione (M8), allyl glutathionyl disulfide (M9), and S-allylglutathione (M10). With the exception of M6, all of the above GSH conjugates were detected in the bile of rats treated with DASO, while only M3, M4, M5, M7, M8, and M10 were found in the bile of rats treated with DASO2. Experiments conducted in vitro showed that GSH reacted spontaneously with DASO to form conjugates M9 and M10, and with DASO2 to form M10. In the presence of NADPH and GSH, incubation of DAS with cDNA-expressed rat CYP2E1 resulted in the formation of metabolites M6, M9, and M10, while incubation with DASO led to the formation of M3, M4, M5, M9, and M10. When DASO2 acted as substrate, CYP2E1 generated only conjugates M3, M4, M5, and M10. These results indicate that while DAS and DASO undergo extensive oxidation in vivo at the sulfur atom, the allylic carbon, and the terminal double bonds, CYP2E1 preferentially catalyzes oxidation of the sulfur atom to form the sulfoxide and the sulfone (DASO and DASO2). However, it appears that the end product of this sequence, namely, DASO2, undergoes further CYP2E1-mediated activation of the olefinic pi-bond, a reaction which transforms many terminal olefins to potent mechanism-based P450 inhibitors. We hypothesize, therefore, that it is this final metabolic event with DASO2 which leads to autocatalytic destruction of CYP2E1 and which is mainly responsible for the chemoprotective effects of DAS in vivo. SN - 0893-228X UR - https://www.unboundmedicine.com/medline/citation/9084912/Metabolism_of_the_chemoprotective_agent_diallyl_sulfide_to_glutathione_conjugates_in_rats_ L2 - https://doi.org/10.1021/tx9601768 DB - PRIME DP - Unbound Medicine ER -