Detoxification Of Electrophilic Xenobiotics

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Various electrophilic xenobiotics, i.e. compounds with centres of low electron density that can accept an electron pair to form a covalent bond, exhibit the tendency to react spontaneously with nucleophilic sites (i.e. centres of electron richness, non-bonded pairs of electrons or bonds) of bio-molecules. Thus, electrophilic xenobiotics may be highly dangerous to the cell, because they are able to bind to proteins and genetic material, i.e. DNA and RNA and thereby disturb metabolic networks.

The action of electrophilic xenobiotics seems to be dependent on their cellular counterparts. There is a preference for the reactions between xenobi-otics and biomolecular partners, which may be explained by the concept of hard and soft nucleophiles/electrophiles (Coleman et al. 1997). In this concept, "hard" and "soft" are attributes of chemical bonds or functions describing the reactivity of the nucleophilic/electrophilic centres. Hence a high degree of polarization with positive or negative charges at the reactive centres characterizes "hard" nucleophiles/electrophiles, whereas "softness" is connected to polarization by low positive or negative charges at reactive sites. The concept is based on the observation that electrophiles and nucleophiles of similar hardness/softness react with each other (Table 1). Consequently, sulphur in peptides (i.e. glutathione) would be the softest nucleophilic site and be able to react with a large number of xenobiotics with corresponding properties.

Table I. Reactivities between nuclcophilic biomolcculcs and clcctrophilic xenobiotics (from Coleman et al. 1997, with modifications).

Nucleophilic site


Electrophilic site

sulphur in cysteinyl residues of


polarized double bonds, aldehydes ^

proteins or GSH

sulphur in inethionyl residues of

epoxides, alkyl sulphates, alkyl


ha 1 ides, stained ring lactones

amino groups in proteins (Arg,

Lys, His)

amino groups of purines in DNA

arylcarbonium ions

and RNA

oxygens of purines and pyri uridi

benzylic carbon ium and nitrenium



phosphate oxygen of RNA and


atkylcarbonium ions


By this ability to spontaneously react with electrophiles, glutathione and its analogues have been suggested to possess a central role as cellular protectants against chemical polarization of soft sulphur containing residues in proteins by xenobiotics.

The mechanism of detoxification is conjugation between the xenobiotic at its electrophilic site and the thio-group of glutathione. This conjugation reaction will proceed spontaneously with a large number of electrophilic xenobi-otics of similar softness. The reaction with hard electrophiles requires additional enzymatic support, which is provided by glutathione S-transferase isoenzymes. In any case detoxification totally depends on the availability of glutathione. The homeostasis of glutathione inside the plant is maintained by a complex regulation process (see other chapters of this volume) with synthesis, degradation and long range transport as visible end points. Perturbation of homeostasis and depletion of GSH pools may therefore lead to severe disturbance in a plant's detoxification capacity.

Prerequisites for glutathione dependent detoxification:

- electrophilic centres on the xenobiotic to be attacked

- adequate supply of glutathione or its analogues

- glutathione S- transferase with respective substrate specificity

Bearing two carboxylic acid groups, one amino group and one thiol group and having two peptide bonds, glutathione is highly hydrophilic. Glutathione conjugation of hydrophobic electrophilic compounds thus leads to a loss of their lipophilicity by converting the parent compound into an amphiphilic product with a bulk hydrophilic region and the non-polar hydrophobic region. This change of physico-chemical properties impedes the mobility of the foreign compound and inhibits further partitioning into membranes as well as the diffusion between compartments. Even more important, the products of this reaction are subject to ionisation at cellular pH and definitely restricted in their availability to the cells and tissues.

In consequence, as has been pointed out recently (Coleman et al. 1997), (a) the biological half-life of the xenobiotic in the cell is decreased, (b) the time the organism is exposed to the toxin is reduced and (c) an accumulation in critical tissues or compartments of the cells is avoided.

However, amphiphilic metabolites have been shown in the literature to act inhibitory on cytoplasmic enzyme action. This might be one of the reasons why the concentration of glutathione conjugates in the cytosol has to be kept low.

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