Biotransformation (Metabolism) of Pesticides - Pesticide Biotransformation and Disposition - page 80

cells and catalyze the NADPH-dependent monooxygenation of pesticides, especially
those with N, S, or P heteroatoms ( Cashman and Zhang, 2006; Ziegler, 2002 ).
Early studies on the contributions of individual CYP isoforms using partially
purified CYP preparations from mouse liver showed considerable variation between
fractions in oxidation of pesticide substrates, in spectral binding, and in inhibition by
piperonyl butoxide ( Beumel et al., 1985; Levi and Hodgson, 1985 ) . Subsequently, the
use of highly purified CYPs from the livers of phenobarbital and β-naphthoflavone-
treated mice showed that these fractions had much higher activity toward the organo-
phosphorus insecticides fenitrothion, parathion, and methyl parathion than did similar
fractions from the livers of untreated mice, suggesting the importance of the CYP1A
and CYP2B families in these oxidations. The isoforms also produced different amounts
of detoxication products compared with the more toxic oxons, with CYP2Bs form-
ing more of the oxon ( Levi et al., 1988 ). Similar studies showed the importance of
the CYP2B family in the hepatic metabolism of phorate to phorate sulfoxide ( Kinsler
et al., 1988, 1990 ). More recently, it has become clear that CYP2B6 is one of the
most important CYP isoforms in the human metabolism of pesticides ( Croom et al.,
2009, 2010; Hodgson and Rose, 2007; Tang et al., 2001 ). This is despite the fact that
CYP3A4 is always the most abundant CYP isoform in the human liver, as the kinetic
constants for CYP2B6 favor its greater involvement.
Studies of in vitro metabolism of pesticides were, until recently, carried out only on
surrogate animals. During the past decade, however, because of the availability of human
liver cells, cell fractions, and recombinant human XMEs, there has been an increas-
ing number of studies of the human metabolism of pesticides, and in some instances,
variations due to polymorphisms have been demonstrated. A summary of pesticide
substrates for human hepatic XMEs is presented in Table 5.3 . It is apparent that essen-
tially all of the human xenobiotic-metabolizing CYPs, as well as some other phase I
enzymes, have one or more pesticide substrates. A number of studies have shown the
importance of both the relative amounts of different CYP or FMO isoforms present
( Buratti and Testai, 2005, 2007; Buratti et al., 2002, 2003, 2007; Cashman and Zhang,
2006; Cherrington et al., 1998b; Mutch et al., 1999, 2003; Yang et al., 2009; Tang et al.,
2001, 2002, 2004; Usmani et al., 2002, 2004a,b; Scollon et al., 2009 ) and the effects of
polymorphisms on the extent of metabolism and the distribution of metabolites ( Dai
et al., 2001; Tang et al., 2001 ). Additional references can be found in Hodgson (2003) .
Other Phase I Enzymes
Epoxide hydrolase is another phase I enzyme known to metabolize pesticides, a well-
known example being the metabolism of the herbicide tridiphane by the epoxide
hydrolase of mouse liver ( Magdalou and Hammock, 1987 ).
The role of carboxylesterases, CYPs, and alcohol and aldehyde dehydrogenases
in the hepatic metabolism of pyrethroids has recently been studied in both rodents