Metabolic Interactions of Pesticides - Pesticide Biotransformation and Disposition - page 157

in rodents, of CYPs 2B and 3A by the herbicide metolachlor ( Dalton et al., 2003 ), of
CYPs 1A and 2B by deltamethrin ( Johri et al., 2006 ), and of a number of CYP-related
metabolic activities by the herbicide alachlor ( Hanioka et al., 2002 ).
DuBois et al. (1996) used hepatocytes from the rat and quail as well as human
hepatoma-derived (HepG2) cells to study the induction of CYP isoforms by pesti-
cides. The pesticides fell into four groups: first, CYP3A inducers such as pentachlo-
rophenol; second, 3-methylcholanthrene-type inducers, such as lindane, an inducer of
CYP1A isoforms; third, phenobarbital-type inducers, such as dieldrin, an inducer of
CYP2B isoforms; and fourth, pesticides with little or no capacity to induce CYP iso-
forms. Pentachlorophenol and lindane were the strongest inducers in these cell lines,
and lindane appeared to be a member of both the second and the third groups because
it induced both CYP1A and CYP2B activities.
Although a small number of studies showed induction by pesticides in rat hepa-
tocytes, for example, the induction of CYP2B1 by pyrethroids ( Heder et al., 2001 ),
the recent availability of human hepatocytes has enabled the investigation of induction
by pesticides in humans ( Das et al., 2006, 2008a,b ). These studies reveal that fipronil
is an effective inducer of CYP1A1, CYP2B6, and CYP3A4 in human hepatocytes,
at concentrations as low as 1.0 μM. The pyrethroids deltamethrin and permethrin,
while not as effective as fipronil, induced the same CYP isoforms. The insecticide
chlorpyrifos and the insect repellent DEET are also capable of inducing xenobi-
otic-metabolizing CYP isoforms in human hepatocytes. All of the results of studies
utilizing human hepatocytes suggest that pesticide-pesticide interactions are possible
in the human liver, and this possibility should be investigated. It might also be noted
that, to a greater or lesser extent, these pesticides are also cytotoxic to human hepa-
tocytes but generally at higher concentrations than those required for CYP isoform
induction.
Of particular concern is the ability of many pesticides to disrupt the normal func-
tioning of the endocrine system, and endocrine disruption has become an impor-
tant environmental concern ( Birnbaum, 1994; Colborn et al., 1993; Guillette et al.,
1994 ). For this reason, many of the recent studies of induction by organochlorines have
involved either methoxychlor or o,p -DDT. Methoxychlor has been shown to induce
CYPs 1A, 2B, 2C, 2E, and 3A in both male and female rats ( Oropeza-Hernandez
et al., 2003 ) and to induce ethoxyresorufin O -deethylase and pentoxyresorufin
O -depentylase activity in HepG2 cells ( Dehn et al., 2005; Medina-Diaz and Elizondo,
2005 ). o,p -DDT and its metabolite o,p -DDE have been shown to induce CYP3A4
( Medina-Diaz et al., 2007 ). The finding that the nuclear receptors pregnane X receptor
(PXR) and constitutive androstane receptor (CAR) are involved in induction in both
HepG2 cells and in immature ovariectomized rats ( Kiyosawa et al., 2008; Wyde et al.,
2003 ) is of mechanistic importance. Lindane has been shown to induce CYPs 1A and
2B in rats ( Johri et al., 2008; Parmar et al., 2003 ).