Introduction to Biotransformation (Metabolism) - Pesticide Biotransformation and Disposition - page 53

metabolic pathways and enzymes that have substrates in several of these use classes.
Phase I involves predominantly oxidations, reductions, and hydrolysis and serves to
introduce a polar group into the molecule. Phase II, consisting primarily of conjuga-
tion reactions, involves the combination of the products of phase I reactions with one
of several endogenous molecules to form water-soluble, and hence excretable, products.
A number of topics review the biotransformation of xenobiotics, either in gen-
eral or of particular chemical or use classes (e.g., Hodgson, 2010; Jakoby, 1980; Jakoby
et al., 1982; Klaassen, 2001; Smart and Hodgson, 2008; Wilkinson, 1976; Williams,
1959 ). Many treatments of pesticides (e.g., Chambers and Carr, 1995; Ecobichon,
2001; Hodgson and Meyer, 1997, 2010; Hodgson et al., 1995; Kulkarni and Hodgson,
1984a,b; Rose et al., 1999 ; Smart and Hodgson, 2008) include considerations, not only
of pesticide metabolism, but also of the significance of metabolism in the toxicity of
pesticides to target and nontarget species.
REACTIONS CATALYZED IN XENOBIOTIC METABOLISM
Many of the chemical reactions involved in the biotransformation of pesticides have
now been traced to particular enzymes (see Chapter 5), although some are only
inferred from the appearance of derivatives of the parent compound in the tissues or
excreta of the dosed animal. Chemical reactions reported to occur in the metabolism
of pesticides are summarized in Figure 4.1 . It should be noted that biotransformation
reactions of pesticides may be either detoxications or activations. Hollingworth et al.
(1995) provided an early detailed review of the detection and significance of the active
metabolites of pesticides. The biotransformation of most pesticides involves a combi-
nation of several chemical reactions and in some instances breakdown products may
become part of the general metabolic pool. For example, formaldehyde formed in
demethylation reactions may be incorporated into the one-carbon metabolic pool.
XENOBIOTIC-METABOLIZING ENZYMES
There are a large number of both phase I and phase II xenobiotic-metabolizing
enzymes, and most exist in the same organism and/or the same tissue as several poly-
morphic forms (Hodgson, 2010). In vertebrates, the liver is the most important locus
for these enzymes although they are found in essentially all tissues.
In the past, most emphasis has been placed on microsomal cytochrome P450
(CYP)-dependent oxidations and reductions of xenobiotics, including pesticides, but
other xenobiotic-metabolizing enzymes are found in mitochondria and in the cytosol
of hepatocytes and other cells. These are discussed below and in subsequent chapters.
More recently, much has been learned of the roles of other phase I enzymes, such as
flavin-dependent monooxygenases (FMO), hydrolases, and epoxide hydrolases, and of