Metabolic Interactions of Pesticides - Pesticide Biotransformation and Disposition - page 158

It is now quite clear that pesticides may have complex effects on the hepatic
monooxygenase system and, in addition to affecting xenobiotic metabolism, pesticides,
by disturbing endogenous metabolism, have the potential to produce profound changes
in both the physiological and the reproductive capacities of the organism ( Birnbaum,
1994; Tyler et al., 1998 ).
Induction of Other Enzymes
Microsomal enzymes are not the only ones subject to induction. For example,
δ-aminolevulinic acid (ALA) synthetase is located in the mitochondria and its activity
may increase 40-100 times in those structures on induction ( Granick, 1965 ).
Interaction between the induction of mitochondrial and that of microsomal
enzymes is illustrated by the action of the pesticide m -dichlorobenzene in rats.
Following daily doses at the rather high rate of 800 mg/kg, there is a biphasic stimula-
tion of ALA-synthetase activity and of the excretion of urinary coproporphyrin, both
of which peak by 3 days and then decline. The decrease in ALA-synthetase and in
excretion of coproporphyrin at 5 days corresponds to the maximal stimulation of drug
metabolism and to a decrease in the concentration of m -dichlorobenzene in the serum
and liver at the same time ( Poland et al., 1971 ).
In the cytosolic fraction of homogenized rat liver, the activity of nicotinamide ade-
nine dinucleotide (NAD)-dependent aldehyde dehydrogenase (EC 1.2.1.3) is increased
up to 10-fold after administration of phenobarbital for 3 days. The effect is genetically
controlled and is inherited as an autosomal dominant characteristic. The mechanism is
apparently unrelated to other drug-induced increases in enzyme activity, such as those
that occur in the hepatic microsomal systems for drug metabolism ( Deitrich, 1971 ).
Glutathione S -transferases as well as CYPs were shown to be induced by pesticides, but
the levels of induction of the former were much lower ( Fabacher et al., 1980; Hodgson
et al., 1980; Kulkarni et al., 1980; Robacker et al., 1981 ).
Mechanism of Induction
Several pesticides have been tested for activation of the PXR receptor in engineered
expression systems ( Lemaire et al., 2006; Matsubara et al., 2007 ). Since human 3A4 is
transcriptionally regulated, in part, by PXR, induction of this CYP is expected for the
pesticides active in the in vitro systems. In rats, one of these compounds, the herbicide
metolachlor, was shown to induce the rat ortholog CYP3A2 as well as CYPB1/2 at
approximately one-fifth the potency of phenobarbital ( Dalton et al., 2003 ). Similarly,
PXR activation by conazole fungicides is supported by activity in the PXR expres-
sion system and from toxicogenomic profile-like signatures of prototype PXR ligands
( Goetz et al., 2006; Tully et al., 2006 ). Similar approaches have defined transcriptional
mechanisms for the pesticide induction of other CYPs through their activity as ligands
for relevant transcriptional activators. Casabar et al. (2010) utilized the HepG2 cell line