Toxicology of Industrial Compounds

66 METABOLISM OF REACTIVE CHEMICALS
thought to be responsible for the covalent binding of 1,2-dichloro- and 1,2dibromoethane
metabolites to protein (Inskeep and Guengerich, 1984).
Glutathione conjugation results in the formation of S-2haloethylglutathione
derivatives, which are sulfur halfmustards and as such
highly reactive metabolites (Jean and Reed, 1989). The formation of these
conjugates is catalyzed by the glutathione S-transferases, and both in rat
and man the alpha-class isoenzymes have been found to be the most
efficient in this catalysis (Cmarik et al., 1990).
The glutathione pathway is responsible for the mutagenicity (Van
Bladeren et al., 1980), the DNA-binding (Koga et al., 1986) as well as very
likely the carcinogenicity (Cheever et al., 1990) of 1,2-dichloro- and 1,2dibromoethane.
The S-2-haloethylglutathione derivatives are strong
alkylating agents (e.g. Jean and Reed, 1989). Their electrophilicity is
attributable to neighboring-group assistance. The halogen atom is displaced
by the sulfur atom on the next carbon atom, to form a highly reactive
episulfonium ion. The intermediacy of this reactive species is supported by
stereochemical studies as well as NMR data (Van Bladeren et al., 1979;
Dohn and Casida, 1987; Peterson et al., 1988).
The relative importance of the oxidative and glutathione-dependent
pathway in vivo is difficult to determine, since both pathways give rise to
the formation of the same 2-hydroxyethylmercapturate. Using
tetradeutero-1,2-dibromoethane, the ratio of the pathways has been
calculated as 4:1 (Van Bladeren et al., 1981b). However, isotope effects
might have a considerable influence on this ratio (White et al., 1983).
The major DNA-adduct derived from 1,2-dibromoethane has been
identified by Guengerich and coworkers to be S-(2-(N7-guanyl)-ethyl)
glutathione (Ozawa and Guengerich, 1983; Koga et al., 1986). In addition,
the structure of one of several minor adducts was recently found to be S-(2-
(Nl-adenyl)ethyl) glutathione (Dong-Hyun et al., 1990). A series of S-2haloethylglutathione
and -cysteine derivatives has been synthesized: all
were found to react with DNA, specifically with guanine residues. As
expected for a mechanism known to involve an intermediate episulfonium
ion, adduct levels were similar for chloro- and bromo-substituted
derivatives. However, in Salmonella typhimurium TA100 a large variation
was observed in the ratio of mutations of adducts, indicating that the
structure of the adduct has a major influence on the mutagenicity
(Humphreys et al., 1990).
Not all vicinal dihaloalkanes seem to give rise to the formation of
episulfonium ions. Methyl substitution for instance effectively hinders the
mutagenicity through this pathway (Van Bladeren, et al., 1981a) and
studies on 1,2-dibromopropane (Zoetemelk et al., 1986) and hexadeuterol,2-dichloro-propane
(Bartels and Timchalk, 1990) indicate that the
resulting mercapturic acids are only formed through an oxidative pathway.
However, for the heavily used agricultural chemical l,2-dibromo-3-