Introduction to Biotransformation (Metabolism) - Pesticide Biotransformation and Disposition - page 61

pesticides with CYP, interactions that may be indicative of the ability to act as substrate
or inhibitor, have also been carried out ( Mailman and Hodgson, 1972; Mailman et al.,
1974 ). Studies using specific isoforms ( Hodgson et al., 1998; Levi and Hodgson, 1984,
1988 ) indicate that even in the same organ of the same species, particular pesticides are
metabolized at different rates by different CYP isoforms.
The specificity of various isoforms for pesticide substrates is an area of current inter-
est. Because of the availability of recombinant human isoforms, these studies can now
be carried out on human enzymes as well as on those from experimental animals. In
an early study of fenitrothion metabolism by mouse liver utilizing four constitutive and
two induced CYP isoforms, Levi and Hodgson (1988) showed that all isoforms pro-
duced both the cresol detoxication product and the oxon. However, there were sig-
nificant differences in both overall activity and the oxon/cresol ratio. The most active
isoform, induced by phenobarbital and now known as CYP2B10, was also active in the
metabolism of parathion and methyl parathion and in all cases produced significantly
more oxon than detoxication products. Human CYP3A4 was shown to be most active
in the metabolism of parathion, although CYP1A2 and 2B6 also showed activity ( Butler
and Murray, 1997 ). In studies on the metabolism of chlorpyrifos by human CYPs ( Tang
et al., 2001 ), it has been shown that CYP2B6, CYP2C19, and CYP3A4 are all active,
CYP2B6 producing an excess of chlorpyrifos oxon and CYP2C19 an excess of detoxi-
cation products, while CYP3A4 produces both in approximately equal quantities.
Studies of the metabolism of triazine herbicides in mice ( Adams et al., 1990 ) and
rats ( Hanioka et al., 1999 ) as well as in rats and pigs ( Lang et al., 1996 ) suggested a
broad lack of isoform specificity for these substrates. However, Lang et al. (1997)
showed that, in humans, CYP1A2 appeared to be the principal, if not the only, iso-
form responsible for triazine herbicide oxidation. A more recent study ( Joo et al.,
2010 ) showed that other CYP isoforms are also be capable of N-dealkylation of atra-
zine (for details see Chapter 5, Table 5.3). Inui et al. (2000) expressed human CYP1A1,
CYP2B6, and CYP2C19 in potatoes and produced resistance to several herbicides,
including atrazine, in the host plants, presumably by enabling the plants to metabolize
the herbicides.
In studies of chloroacetanilide herbicides ( Coleman et al., 1999 ), it was shown that
human CYP3A4 was responsible for the initial O -dealkylation of alachlor. Subsequent
studies ( Coleman et al., 2000 ) extended these studies to acetochlor, butachlor,
and metachlor. In all cases, CYP3A4 was the most active human isoform, although
CYP2B6 also had some activity.
One of the significant features of many of the microsomal CYPs is their inducibil-
ity by xenobiotics; thus, stimulation of the metabolism of a chemical by prior admin-
istration of the same or another chemical is often taken as presumptive evidence of its
metabolism by microsomal enzymes. For example, in mice pretreated with phenobar-
bital there is an increase in phorate metabolism, suggesting that CYP isoforms, such as