Review
Biological targets of isothiocyanates

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Abstract

Background

Isothiocyanates are phytochemicals with a broad array of effects in biological systems. Bioactivity includes the stimulation of cellular antioxidant systems, induction of apoptosis and interference with cytokine production and activity. Epidemiological evidence and experimental studies indicate that naturally occurring isothiocyanates and synthetic derivatives have anti-cancer and anti-inflammatory properties.

Scope of review

This review focuses on the molecular targets of isothiocyanates, and how target modification translates into a biological response.

Major conclusions

Isothiocyanates may mediate their effects via direct protein modification or indirectly by disruption of redox homeostasis and increased thiol oxidation. Some target proteins have been identified, but in-depth searches with new techniques are needed to reveal novel targets. Site-directed mutagenesis and isothiocyanate structure-activity relationships will assist in determining the biological significance of specific modifications.

General significance

Target identification is important for rational drug design and exploiting the therapeutic potential of isothiocyanates. It also provides insight into the diverse pathways that these compounds regulate.

Highlights

► Plant-derived isothiocyanates modify biological processes. ► Protein microenvironment promotes selective isothiocyanate reactivity. ► Probes are revealing previously unidentified targets.

Introduction

Naturally-occurring isothiocyanates are a class of secondary metabolite responsible for the bitter taste and pungent odour of cruciferous vegetables such as broccoli, watercress, mustard and wasabi [1], [2]. Disruption of plant tissue results in the hydrolysis of inert glucosinolates by the enzyme myrosinase (Fig. 1). The resultant isothiocyanates are proposed to play a key role in plant-pathogen interactions [3], [4]. Isothiocyanates have also attracted attention for the prevention and treatment of human disease. Humans obtain isothiocyanates through the consumption of cruciferous vegetables, with plasma levels reaching low micromolar concentrations [5], [6]. Epidemiological evidence indicates a positive association between increased consumption of cruciferous vegetables and decreased cancer risk [7], [8], [9], and animal studies have shown anti-cancer properties [10], [11], [12].

Isothiocyanates are reactive electrophiles that covalently modify proteins. This property has been utilised in research laboratories for tagging proteins with compounds such as fluorescein isothiocyanate, and for protein sequencing by Edman degradation, which utilises the reaction of phenyl isothiocyanate with the N-terminal amine of peptides and proteins. Protein modification will also be central to the effects of isothiocyanates in biological systems. These effects include triggering noxious responses, influencing carcinogen metabolism, impairing tumour development and modifying inflammatory cytokine production, and have been discussed in more comprehensive reviews [13], [14], [15], [16]. Here we focus on current knowledge of initial isothiocyanate targets and how protein modification translates into biological responses.

Section snippets

Isothiocyanate reactivity

The central electrophilic carbon of isothiocyanates (Rsingle bondNdouble bondCdouble bondS) undergoes rapid addition reactions with biological nucleophiles, in particular, amines and thiols [17]. Isothiocyanates react with amines to generate stable thiourea derivatives, whereas reaction with thiols generates labile dithiocarbamate adducts (Fig. 2). Seminal studies by Drobnica and colleagues through the 1970's characterised the reactivity of a variety of isothiocyanates with small molecules, peptides and proteins, and showed

Noxious responses

Given that glucosinolate hydrolysis is activated in response to plant damage, it has been hypothesised that a major function of the resultant metabolites is to defend against attack from herbivores and pathogens. Isothiocyanates can act as poisons or deterrents towards herbivores [3], [30], bacteria [31] and fungi [32], [33]. When applied to the skin, they elicit a noxious response. The pain and inflammation induced by topical application of isothiocyanates is mediated via depolarization of a

Physiological reactions of isothiocyanates: indirect disruption of redox homeostasis

Many structural and regulatory proteins have critical cysteine residues that are susceptible to oxidation. As a consequence, cells require a network of antioxidants to maintain a reducing environment. Some of these antioxidant proteins use reactive cysteine or selenocysteine residues to catalyse the breakdown of oxidants, and are susceptible to inactivation by electrophiles. Isothiocyanates could therefore mediate their effects indirectly by disrupting antioxidant networks, and increasing

Summary

Many of the drugs used to successfully treat human disease have been derived from nature [110]. Billions of years of natural selection have produced potent chemicals with the ability to diffuse through tissues, cross membranes and modify proteins within complex biological systems. Isothiocyanates produced by cruciferous plants have strong bioactivity, and their therapeutic properties are being actively explored. Isothiocyanates are also providing insight into fundamental cell signalling

Acknowledgements

This work was supported by the Cancer Society and the Health Research Council of New Zealand. We would like to thank Dr Joel Tyndall for producing Fig. 4.

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