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with glucuronic acid to form glucuronides, N -acetylcysteine to form mercapturic
acids, glycine to form hippuric and related acids, sulfate to form ethereal sulfates, thio-
sulfate ions to form thiocyanate, and glutamine to form conjugates of the same name.
In fact, the actual conjugations often occur with derivatives of the conjugating mol-
ecule, for example, with glutathione, uridine diphosphate glucuronic acid, or phospho-
adenine phosphosulfate. Conjugates of foreign chemicals that are rare in mammals, or
known only in other classes or phyla, include glucosides, ribosides, ornithines, sulfides,
and conjugates with serine, metal complexes, and methylated or acetylated compounds.
Ethereal sulfates, while less important in the metabolism of pesticides than glucuro-
nides, nevertheless may be formed from carbofuran and other carbamates ( Dorough,
1968 ). Glutathione conjugation is important in the metabolism of organophosphates
( Motoyama and Dauterman, 1980 ) and the conjugated products of glutathione adducts
may be further metabolized to mercapturic acids, the N -acetylcysteine derivative of
the original xenobiotic substrate. Insects and plants are unusual in forming glucosides
rather than glucuronides. A general review of phase II metabolism of xenobiotics is
that of LeBlanc (2008) .
With the exception of glutathione conjugation, most conjugation reactions involving
pesticides are secondary, involving, as substrates, the products of phase I reactions. They
include glucoside formation, glucuronic acid formation, sulfate formation, and conjuga-
tion with amino acids. This area, as it applies to pesticides, is reviewed in Chapter 5.
Glutathione S -Transferases
Conjugation with glutathione, mediated by one of the glutathione S -transferases, is the
first step in a sequence leading to a mercapturic acid ( Figure 4.1 ). Several pesticides
are metabolized in this way, particularly organophosphorus compounds, DDT, γ-HCH,
and organothiocyanates. These reactions and their relationship to pesticides have been
reviewed by Motoyama and Dauterman (1980) and by Fukami (1984) .
The glutathione S -transferases (GSTs) are an abundant family of dimeric proteins
that have the capacity to conjugate glutathione with a variety of compounds contain-
ing electrophilic centers. The major hepatic cytosolic GSTs in mammalian liver can
be divided into three classes—Alpha (α), Mu (μ), Pi (π)—based on sequence simi-
larity and catalytic activity ( Mannervik et al., 1985 ). Each class may contain one or
more functional enzymes. Although all of these classes are capable of binding to a
wide variety of pesticides, the Mu class has somewhat higher affinity than the Alpha
or Pi class ( Dillio et al., 1995; Hayes and Wolf, 1980 ). Members of the Mu class of
GSTs are responsible for conjugating benzo[ a ]pyrene-7,8-diol-9,10-epoxide as well
as a wide variety of pesticides such as the organophosphate insecticides, the haloge-
nated hydrocarbon insecticides, and the S -triazine herbicides ( Hayes and Wolf, 1980 ).
Polymorphisms are known to occur in humans in regard to GST enzymes. About 50%
of the Caucasian population in the United States is deficient in Mu-class GSTM1.
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