Citation

Brady JF, Ishizaki H, Fukuto JM, Lin MC, Fadel A, Gapac JM, Yang CS. Chem. Res. Toxicol. 1991; 4(6): 642-647.

Copyright

(Copyright © 1991, American Chemical Society)

DOI

10.1021/tx00024a008

PMID

1807447

Abstract

Diallyl sulfide, a major flavor ingredient from garlic, was previously shown to inhibit chemically induced carcinogenesis and cytotoxicity in animal model systems. It modulated cytochrome P-450 compositions by inactivating P-450 2E1 and inducing P-450 2B1. The present studies examined the inhibition of P-450 2E1 mediated p-nitrophenol hydroxylase activity by diallyl sulfide and its putative metabolites diallyl sulfoxide and diallyl sulfone (DASO2). Each compound displayed competitive inhibition of p-nitrophenol hydroxylase activity in incubations using liver microsomes from acetone-pretreated male Sprague-Dawley rats. Preincubation of the microsomes with DASO2 inactivated p-nitrophenol hydroxylase activity in a process that was time- and NADPH-dependent and saturable, exhibited pseudo-first-order kinetics, was protected by alternate substrate, was accompanied by a loss of microsomal P-450-CO binding spectrum, and was unaffected by exogenous nucleophile. The Ki value for DASO2 was 188 microM and the maximal rate of inactivation was 0.32 min-1. DASO2 was ineffective in the inactivation of ethoxyresorufin dealkylase, pentoxyresorufin dealkylase, or benzphetamine demethylase activity. Purified P-450 2E1 in a reconstituted system was inactivated in a time- and NADPH-dependent manner by DASO2. The metabolic conversion of diallyl sulfide to the sulfoxide and sulfone was observed in vivo and in vitro. The results suggest that diallyl sulfide inhibits the metabolism of P-450 2E1 substrates by competitive inhibition mechanisms and by inactivating P-450 2E1 via a suicide-inhibitory action of DASO2.

Language: en

Keywords

Allyl Compounds; Animals; Cytochrome P-450 CYP2E1; Cytochrome P-450 Enzyme Inhibitors; Male; Mixed Function Oxygenases; Rats; Rats, Inbred Strains; Sulfides; Sulfones; Sulfoxides