Elsevier

Methods in Enzymology

Volume 382, 2004, Pages 449-456
Methods in Enzymology

Induction of Phase II Enzymes by Aliphatic Sulfides Derived from Garlic and Onions: An Overview

https://doi.org/10.1016/S0076-6879(04)82024-XGet rights and content

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This chapter analyzes the induction of phase II enzymes by aliphatic sulfides derived from garlic and onions. Some Allium-derived sulfides are potent inducers of phase II enzymes in rodents. It is suggested that allyl sulfides are involved in the chemoprotective action of garlic, but compounds of comparable activity have not been isolated from onion. Most of the studies to date have involved short-term administration of Allium-derived sulfides. Several experiments on phase II enzyme induction by Allium-derived sulfides have been reported. In all cases, rats or mice have been employed. Many dosing protocols have been used, with a wide range of dose levels, duration of dosing and route of administration. Most studies have employed oral dosing, either by intubation or by dietary feeding, although some have involved injection of the test materials. In most studies, the focus is on sulfides that are commercially available. From these studies, the importance of unsaturation in the alkyl chain was confirmed, with both the allyl and prop-1-enyl derivatives showing a higher level of induction in many tissues than the propyl. The importance of the number of sulfur atoms in the molecule was also confirmed, although the direction of the effect was different in the allyl and prop-1-enyl sulfides.

Introduction

Plants of the Allium family, such as garlic and onions, have been cultivated for food since earliest times.1 They have also been employed in folk medicine in many parts of the world.1 More recently, epidemiological studies have indicated a chemoprotective effect of both onions and garlic, with individuals consuming large amounts of these vegetables showing a lower incidence of cancer, particularly cancer of the stomach and intestine, than those consuming only small amounts.2 These findings have stimulated much research into the active components of garlic and onions and the mechanism of their chemoprotective action. Allium plants contain high concentrations of alk(en)yl cysteine sulfoxides. Garlic and its relatives contain predominantly allyl cysteine sulfoxide, while onions, shallots and leeks contain the methyl, propyl and prop-1-enyl derivatives.3 When the tissue is disrupted by cutting, crushing or chewing, the cysteine sulfoxides are enzymatically degraded to sulfenic acids. The sulfenic acids decompose spontaneously. Allyl, methyl and propyl sulfenic acids yield mainly thiosulfinates, while prop-1-enyl sulfenic acid forms both the corresponding thiosulfinate and thiopropanal S-oxide, the onion lachrymatory factor. Thiosulfinates themselves are unstable, particularly on heating, and break down to a complex mixture of compounds, in which mono-, di-, tri- and tetra-sulfides predominate.4, 5 Both symmetrical and mixed sulfides are formed. The structures of the symmetrical methyl, propyl, allyl and prop-1-enyl sulfides are shown in Fig. 1.

Several of the sulfides formed from the thiosulfinates present in onion and garlic have been shown to protect against a variety of chemical carcinogens in experimental animals, and it has been suggested that such substances are responsible for the chemoprotective action of these vegetables.6, 7, 8 Furthermore, it has been proposed that this effect is due, at least in part, to the ability of these sulfides to increase tissue activities of phase II detoxification enzymes.9, 10 These enzymes, which include glutathione S-transferase (GST, EC 2.5.1.18), epoxide hydrolase (EH, EC 3.3.2.3), quinone reductase (QR, DT-diaphorase, NAD[P]H:quinone-acceptor oxidoreductase, EC 1.6.99.2) and UDP-glucuronosyl transferase (UDPGT, EC 2.4.1.17), inactivate many electrophilic substances, including certain carcinogens, and facilitate their elimination from the body.11 Many experiments have been conducted on the ability of Allium-derived sulfides to increase tissue activities of phase II enzymes in animal models, and these experiments, and their relevance to the human situation, are the subject of the present review.

Section snippets

Materials and Assay Methods

Some Allium-derived sulfides are commercially available. Pure dimethyl, diallyl and dipropyl monosulfides and dimethyl and dipropyl disulfide may be obtained from several suppliers (e.g., Acros, Lancaster, Aldrich), while diallyl trisulfide is available from LKT Laboratories. Diallyl disulfide is also sold by many suppliers, but it should be noted that the commercial product contains only 75% to 80% of the disulfide; the remainder is largely diallyl sulfide12 or diallyl trisulfide.13 Pure

Phase II Enzyme Induction by Allium-Derived Sulfides

Twenty-seven experiments on phase II enzyme induction by Allium-derived sulfides have been reported (see 9, 26, 27, 28, 29, 30 and literature cited therein). In all cases, rats or mice have been employed. Many dosing protocols have been used, with a wide range of dose levels, duration of dosing and route of administration. Most studies have employed oral dosing, either by intubation or by dietary feeding, although some have involved injection of the test materials. Most studies have focused on

Relevance of Animal Studies to the Human Situation

If phase II enzyme induction by sulfides is involved in the chemopreventative action of Allium vegetables, it would be expected that effects would be seen in animal models at doses similar to those that could be obtained from dietary intake of these vegetables by humans, and that induction would be seen in those tissues which epidemiological studies show a decrease in cancer incidence.

The average daily intake of garlic in the USA is 1.4 g⧸day,32 while individuals with a high intake of this

Toxicity of Sulfides and Relationship to Mechanism of Enzyme Induction

Di-, tri- and tetra-sulfides cause hemolytic anemia in laboratory and domestic animals.30, 38 In the presence of reduced glutathione, these substances undergo redox cycling, with concomitant production of “active oxygen” species. The latter species are held responsible for initiating the erythrocyte damage leading to hemolysis.

The induction of phase II enzymes by many substances, of diverse chemical structure, has been shown to involve transcriptional gene activation through covalent alteration

Conclusions

Some Allium-derived sulfides are potent inducers of phase II enzymes in rodents. It is possible that allyl sulfides are involved in the chemoprotective action of garlic, but compounds of comparable activity have not been isolated from onion. Most of the studies to date have involved short-term administration of Allium-derived sulfides. Since humans consume Allium vegetables regularly throughout their lives, and since the degree of enzyme induction may increase with prolonged exposure, more work

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