Toxicology of Industrial Compounds

P.J.VAN BLADEREN AND B.VAN OMMEN 63
serve as transporting and targeting agents for compounds that react
reversibly with gluathione such as isothiocyanates, isocyanates and α,
βunsaturated
ketones (Van Bladeren, 1988).
Glutathione S-transferase polymorphism
Genetic variation in the expression of GST isoenzymes has been studied
almost solely in man. Considerable variation, possibly indicating a
polymorphism, has been observed for the human liver alpha class
isoenzymes. The ratio of GSTA1 and GSTA2 subunits, as determined by
HPLC, was found to range from 0.5 to over 10 (Van Ommen et al., 1990).
However, a division into two groups, with average ratios of 1.6±0.3 and 3.
8±0.6 could be made, suggesting an alpha class polymorphism. In view of
the fact that subunits GSTA1 and GSTA2 together make up a major
portion of the GST protein in human liver this potential polymorphism
merits further attention. For class mu isoenzymes a clear polymorphism
has been observed in humans: iso-enzyme GSTM1a-1a was found to be
expressed in only 60% of the samples analyzed (Board, 1981). In this study
no account was taken of the fact that a second mu class isoenzyme,
isoenzyme GSTM1b-1b was also suggested to play a part in this
polymorphism. In a study on the excretion of the mercapturate derived
from 1,3-dichloropropene in exposed workers, however, no difference was
observed between mu-positive and mu negative subjects (Vos et al., 1991).
Quinones and their glutathione conjugates
Two modes of reactivity can form the basis of the toxicity associated with
quinones: (i) their ability to undergo ‘redox cycling’ and to thereby create
an oxidative stress (Kulkarni et al., 1978), and (ii) their electrophilicity
allowing them to react directly with cellular nucleophiles such as protein
and non-protein sulfhydryls (Dierickx, 1983). Since glutathione is the
major non-protein sulfhydryl present in cells, it comes as no surprise that it
is intimately involved in the biological effects of quinones. On the one
hand, glutathione can act as a reducing agent, detoxifying quinones by
converting them to hydroquinones with the concomitant formation of
glutathione disulfide. On the other hand quinone and hydroquinonethioethers
are formed. Recently considerable evidence has been gathered,
indicating that a variety of these thioethers possess biological activity
(Dierickx, 1983; Koga et al., 1986).
The target sites for the biological (toxicological) activity of
quinonethioethers is to a large extent determined by the glutathione moiety:
as will be discussed, the main targets are the kidney (Monks et al., 1985)
and various enzymes using glutathione as a (second) substrate, e.g. the
glutathione S-transferases (Van Ommen et al., 1988). Bromobenzene is