Biotransformation (Metabolism) of Pesticides - Pesticide Biotransformation and Disposition - page 92

Several studies have reported activity of known FMO substrates by brain micro-
somes ( Bhamre et al., 1993; Duffel and Gillespie, 1984; Kawaji et al., 1994 ), and one
form of FMO has been demonstrated using polymerase chain reaction amplification
( Blake et al., 1996 ).
Gastrointestinal Tract
Xenobiotic metabolism in the gastrointestinal tract has been reviewed by Ding and
Kamienski (2003) . Some carbaryl is hydrolyzed and the resulting naphthol is conju-
gated with glucuronic acid by the intestine ( Pekas and Paulson, 1970 ), and Furnes and
Schlenk (2005) have demonstrated sulfoxidation of fenthion by FMO in the intestine.
METABOLISM IN HUMANS
For several reasons, pesticide metabolism in humans is a rapidly increasing area of
research. Since approximately 2000, human hepatocytes, human cell lines, human
cell fractions, and recombinant human xenobiotic-metabolizing enzymes have
become increasingly available and, as a result, ethical experiments can be carried out
without risk. Prior to that time pesticide metabolism was studied in surrogate ani-
mals, primarily rodents, and the results, for regulatory purposes, were extrapolated to
humans. Utilizing human materials directly avoids this extrapolation and, at the least,
helps in selecting the most appropriate surrogate animal. Of equal importance is the
investigation of variation in the human population, the identification of subgroups
or individuals in the population potentially at greater risk, and the identification of
human-specific interactions; things that cannot be done in surrogate animals.
Much of the variation in xenobiotic metabolism in humans is due to the occur-
rence of most, if not all, xenobiotic-metabolizing enzymes in a number of polymor-
phic forms. A polymorphism is defined as an inherited monogenetic trait that exists
in the population in at least two genotypes (two or more variant alleles) and is stably
inherited. Several modified alleles may occur at the same gene locus, and population
differences in the incidence of polymorphisms are known to occur in pesticide-
metabolizing CYPs ( Hodgson and Croom, 2008 ). Single-nucleotide polymorphisms
and their effects have been intensively studied in the metabolism of clinical drugs but
there are, as yet, few such studies on the metabolism of pesticides. To date these stud-
ies have shown the importance of polymorphic forms in the metabolism of carbaryl,
carbofuran and sulprofos by CYP2C9 and chlorpyrifos by CYP2B6, CYP2C19, and
CYP3A4 ( Dai et al., 2001; Tang et al., 2001, 2002; Usmani et al., 2004a,b; Rose et al.,
2005; Croom et al., 2010 ).
The human metabolism of pesticides is included in the preceding sections and
some examples are given in Table 5.1 . However, because of the important and topi-
cal nature of this subject, the enzymes involved in human phase I metabolism of