Metabolic Interactions of Pesticides - Pesticide Biotransformation and Disposition - page 156

Another group of pesticides, the phenoxyacetic acid herbicides (e.g., 2,4-dichloro-
phenoxyacetic acid), and the herbicide synergist tridiphane were found to induce the
CYP4A isozymes in rodents ( Levi et al., 1992; Moody et al., 1987, 1992 ). These CYP
isoforms are known to be involved in the oxidation of fatty acids and the mainte-
nance of lipid homeostasis. Moreover, in rodents, compounds that are CYP4A inducers
also cause peroxisome proliferation, an event associated with nongenotoxic induction
of liver tumors in rodents. Another peroxisome proliferator, the fenvalerate metabolite
fenvaleric acid, has been shown to induce several CYP-dependent enzyme activities
including 7-ethoxyresorufin de-ethylation, catalyzed by CYP1As; 7-pentoxyresorufin
O-dealkylation, catalyzed by CYP2Bs; and testosterone hydroxylation, catalyzed by
CYP3A and CYP2B11 ( Morisseau et al., 1991 ). The exact relationship of these inter-
actions and the relevance to humans has not yet been defined.
Methylenedioxyphenyl (MDP) compounds, such as piperonyl butoxide and sesa-
mex, have been used as synergists with pyrethroid and carbamate pesticides. Other
well-known MDP compounds such as safrole and isosafrole are found in many com-
mon foods of plant origin. These chemicals affect multiple enzyme pathways, including
the CYP system ( Hodgson and Philpot, 1974 ). Their effect on CYP enzymes is bipha-
sic, that is, inhibition followed by induction, and is discussed more fully under Biphasic
Effects: Inhibition and Induction. Reviews include those of Philpot and Hodgson
(1971-1972) , Hodgson and Levi (1998) , and Hodgson (1999) . However, MDP com-
pounds are known to induce both enzyme and mRNA for several CYP isoforms in
the mouse, including CYP1A1, CYP1A2, and CYP2B10. CYP1A2 is induced by
both Ah-receptor-dependent and Ah-receptor-independent mechanisms ( Cook and
Hodgson, 1985, 1986; Ryu et al., 1995, 1996 ).
The fungicide captan, although inhibiting many hepatic CYP-dependent activities
in mouse liver ( Paolini et al., 1999 ), induces both CYP3A and CYP1A2 in the kidney
and CYP1A2 in the lung. The ergosterol biosynthesis inhibiting fungicides (EBIFs), for
example, clotrimazole and propioconazole, have been shown to have multiple effects
on the rodent CYP system ( Ronis et al., 1994 ). The EBIFs induced CYPs 3A, 2B,
and 1A, while suppressing the activity of CYP2C11. These alterations were found to
cause significant changes in testosterone metabolism in male rats. Cellular techniques
are becoming more available for the study of induction by pesticides.
The azole fungicides have been shown to be inducers of various XMEs, primarily in
rodents ( Allen et al., 2006; Barton et al., 2006; Martin et al., 2007; Sun et al., 2006, 2007;
Ward et al., 2006 ).
Among recent studies of interest is the demonstration of the induction of
CYP4A10 and CYP4A14 in mice by the pesticide adjuvant, Toximul, an effect medi-
ated through the PPARα receptor ( Upham et al., 2007 ). Diuron and related phenyl-
urea herbicides induced CYP1A1 via the Ah receptor in several cell lines, including
at least one human cell line ( Zhao et al., 2006 ). Further studies showed the induction,