Metabolic Interactions of Pesticides - Pesticide Biotransformation and Disposition - page 165

and Murray, 1997 ). The activities inhibited included testosterone 6β-hydroxylation,
catalyzed by CYP3A4; 7-ethoxyresorufin deethylation, catalyzed by CYP1A2; and tol-
butamide methyl hydroxylation, catalyzed by CYP2C9/10. Aniline 4-hydroxylation,
catalyzed by CYP2E1, was not inhibited.
The inhibition of CYP-dependent monooxygenations by organophosphorus insec-
ticides may be of considerable importance in human health risk assessment, as it has
been shown that organophosphorus insecticides containing the P  S moiety are potent
inhibitors of the human microsomal metabolism of both testosterone and estradiol
( Usmani et al., 2003, 2006 ).
Organophosphorus compounds may also inhibit enzymes other than CYP, par-
ticularly esterases (e.g., Cohen, 1984; Gaughan et al., 1980 ). Gaughan et al. (1980) also
showed that profenofos, EPN, and S,S,S -tributylphosphorotrithioate, when administered
in vivo to mice, all inhibited the liver microsomal esterases hydrolyzing trans -permethrin
as well as the carboxylesterase hydrolyzing malathion. Chlorpyrifos oxon is a potent
inhibitor of the hydrolysis of pyrethroids by human liver preparations ( Choi et al., 2004 ).
While malathion is the safest organophosphorus insecticide in current use, the pres-
ence of isomalathion, an occasional contaminant in commercial preparations, creates a
serious toxicity situation because of the ability of isomalathion to inhibit the carbox-
ylase that detoxifies malathion. This permits an increase in in vivo levels of malathion,
which can then be metabolized, by CYP-dependent oxidative desulfuration, to the
potent acetylcholinesterase inhibitor malaoxon ( Jensen and Whatling, 2010 ).
The fungicide captan, apparently through reactive metabolites, inhibits several CYP-
dependent enzyme activities in mouse liver ( Paolini et al., 1999 ), although it induces
the 2α-hydroxylation of testosterone. Methoxychlor, again through a reactive interme-
diate, inhibits the oxidation of both testosterone and estradiol, the pattern of metabolites
indicating inhibition of CYP2C11 in rats and CYP3A in humans ( Li et al., 1993 ).
It may also be noted that nonpesticidal inhibitors of CYP isoforms may affect
the metabolism and toxicity of pesticides. For example, Agyeman and Sultatos (1998)
showed that the H2-blocker cimetidine caused a moderate increase in the toxicity of
parathion but did not affect the toxicity of paraoxon, an effect brought about by the
inhibition of CYP isoforms.
BIPHASIC EFFECTS: INHIBITION AND INDUCTION
Many inhibitors of mammalian CYP-dependent monooxygenase activity can also act
as inducers. Generally, inhibition of microsomal monooxygenase activity is fairly rapid
and involves a direct interaction with the cytochrome, whereas induction is a slower
process. Therefore, after a single injection an initial decrease due to inhibition is fol-
lowed by an inductive phase. As the compound and its metabolites are eliminated, the
levels of activity return to control values.