Pesticide Excretion - Pesticide Biotransformation and Disposition - page 185

( Tribull et al., 2003 ), bind to human MRP1, and Mrp1 knockout mice are more
sensitive to the toxic effects of methoxychlor. Based on studies of a p -glycoprotein
polymorphism, it has been suggested that p -glycoprotein plays a protective role in
Parkinson's disease ( Drozdzik et al., 2003 ).
On the basis of their ability to inhibit the p -glycoprotein-mediated efflux of doxo-
rubicin, several pesticides of different chemical classes were shown to bind to human
p -glycoprotein ( Bain and LeBlanc, 1996 ). The most effective were the organochlorines
chlordecone, endosulfan, heptachlor and heptachlor epoxide, and the organophos-
phorus insecticides chlorpyrifos, chlorthiophos, dicapthon, leptophos, parathion, and
phenamiphos, as well as clotrimazole and ivermectin. None of the carbamates or pyre-
throids tested were effective. Lipophilicity and molecular mass were the major deter-
minations of pesticide binding, with log K ow values of 3.6-4.5 and molecular masses
of 391-490 Daltons being optimal. The authors pointed out that the ability to inhibit
p -glycoprotein function does not necessarily mean that the chemical will be trans-
ported. Only endosulfan, the compound with the best binding characteristics, could
be shown to be transported by p -glycogen. A study of four insecticides ( Sreeramula
et al., 2007 ), methylparathion, endosulfan, cypermethrin, and fenvalerate, demonstrated
that all four stimulated p -glycoprotein ATPase activity at low concentrations. At higher
concentrations the stimulation was lower or, in the case of methylparathion, inhibi-
tory. It was further demonstrated that all of these insecticides inhibited the transport
of a known ligand for p -glycoprotein, tetramethylrosamine. Other recent studies have
shown that several pesticides were able to inhibit the uptake of a model p -glycopro-
tein substrate, calcein acetoxymethyl ester, into NIH 3T3 mouse fibroblasts stably
transfected with the human MDR1 gene ( Pivcevic and Zaja, 2006 ). Of the 14 pesti-
cides tested, endosulfan, phosalone, and propioconzole were the most active. Similarly,
rotenone, diazinon, and atrazine inhibited the efflux of taxol from the basolateral to
the apical side of Caco-2 cells, and rotenone and diazinon inhibited estradiol-17β-
glucuronide uptake into MRP2-expressed membrane vesicles, while rotenone was a
potent inhibitor of estradiol sulfate uptake into BCRP-expressing membrane vesicles
( Pulsakar et al., 2006 ).
The possibility that p -glycoprotein is related to insect resistance to insecticides
( Buss et al., 2002; Buss and Callaghan, 2008; Lanning et al., 1996a,b ) has not been fully
explored and, although probable, remains hypothetical.
EXCRETION OF PESTICIDES AND THEIR METABOLITES AS
BIOMARKERS OF EXPOSURE
There have been a number of studies using urinary pesticides or their metabo-
lites as biomarkers of exposures. The early studies in this area were summarized in
1989 ( Wang et al., 1989 ), and since then some of the associated problems have been