Introduction to Biotransformation (Metabolism) - Pesticide Biotransformation and Disposition - page 64

oxon formation by CYPs ( Smyser and Hodgson, 1985; Smyser et al., 1985 ) as well
as the oxidation of pesticides from a number of different chemical classes ( Tynes and
Hodgson, 1985 ). Reviews include Hodgson (1982-1983) , Kulkarni and Hodgson
(1984a,b) , and Hodgson et al. (1998) . FMO isoform specificity in pesticide metabolism
is also being investigated. For example, Cherrington et al. (1998a,b) showed that, in the
mouse, FMO1 metabolizes phorate to phorate sulfoxide but FMO5 is without activity.
A recent review ( Hodgson et al., 2008 ) covers aspects of xenobiotic metabolism by
the FMO.
Other Phase I Enzymes
Epoxide Hydrolases
Epoxide rings of certain alkene and arene compounds are hydrated enzymatically by
epoxide hydrolases to form the corresponding trans -dihydrodiols. The epoxide hydro-
lases are a family of enzymes known to exist both in the endoplasmic reticulum and in
the cytosol. The overall attributes of these enzymes are discussed in Arand et al. (2005)
and Hodgson et al. (2008) .
Epoxide hydrolases are known to attack xenobiotics of many classes, including some
pesticide substrates, although these reactions are subsequent to the initial formation of
epoxides. Examples include naphthalene 1,2-oxide and the 3,4- and 5,6-epoxides of
carbaryl ( Dorough and Casida, 1964 ) and tridiphane ( Magdalou and Hammock, 1987 ).
Prostaglandin Synthetase
Prostaglandins are synthesized in mammals via a reaction sequence starting with ara-
chidonic acid as substrate. During the second, or peroxidase, step of prostaglandin
synthetase action, xenobiotics can be co-oxidized to yield products similar to those
formed by various isoforms of CYP ( Eling et al., 1983; Hodgson et al., 2008; Marnett
and Eling, 1983 ). A number of pesticides (e.g., aminocarb, parathion) have been shown
to act as substrates. These reactions may be important in extrahepatic tissues low in
CYP and high in prostaglandin synthetase, such as the seminal vesicle and the inner
portion of the medulla of the kidney.
Aldehyde Oxidase
Aldehyde oxidase is a molybdenum-containing oxidoreductase that is similar to xan-
thine oxidase, also a molybdoenzyme. The extent to which either is involved in pes-
ticide metabolism is uncertain, although it is clear that aldehyde oxidase plays a role
in the metabolism of neonicotinoid insecticides ( Shi et al., 2009 ). The metabolism of
specific pesticides by this enzyme is summarized in Chapter 5. Aldehyde oxidase is
cytosolic and appears, with the exception of the liver, to be expressed in most tissues
to a relatively low extent. Aldehyde oxidase oxidizes aldehydes to their corresponding