Introduction to Biotransformation (Metabolism) - Pesticide Biotransformation and Disposition - page 59

and smooth endoplasmic reticulum. The specific activity of smooth microsomes is
generally higher than that of rough microsomes for the metabolism of xenobiotics.
However, even though rough and smooth microsomes can be separated by density gra-
dient centrifugation, this is generally not done in pesticide metabolism investigations.
The cytosol may be defined as the postmicrosomal supernatant following differen-
tial centrifugation of a cell or tissue homogenate.
The majority of studies focusing on pesticide metabolism and the regulation of pes-
ticide-metabolizing enzymes have been conducted in experimental animals, primarily
rodents. However, there has been an increase in information about human enzymes,
especially the CYP isoforms. Much of this information has been gained through the
use of specific substrates, antibodies, human hepatocytes, human cell fractions, and
recombinant human enzymes. Studies with human CYPs have become more common
and have demonstrated that xenobiotic metabolism and the regulation and expression
of xenobiotic-metabolizing enzymes may be quite different in humans and in experi-
mental animals. Such differences make the extrapolation of metabolism studies from
experimental animals to humans difficult. It is only as we learn to understand these dif-
ferences that we can make more accurate and realistic extrapolations to humans.
PHASE I XENOBIOTIC-METABOLIZING ENZYMES
Cytochrome P450 Monooxygenases
Although several enzymes acting in concert may be required for xenobiotic degrada-
tion or activation, the initial reaction usually involves a microsomal phase I enzyme
catalyzing an oxidation reaction. Reduction reactions, although they may also occur,
are relatively uncommon. These enzymes include many of the isoforms of CYP active
in the CYP-dependent monooxygenase system, as well as FMO isoforms. The overall
aspects of the biochemistry and molecular biology of the CYP system are discussed in
detail by Zeldin and Seubert (2008) .
Many different pesticide mono-oxygenation reactions are attributed to CYPs,
including epoxidation (e.g., aldrin), N -dealkylation (e.g., alachlor, atrazine),
O -dealkylation (e.g., chlorfenvinphos), S -oxidation (e.g., phorate), and oxidative desul-
furation (e.g., parathion) ( Hodgson, 1982-1983; Kulkarni and Hodgson, 1980, 1984a,b ).
They are discussed in detail in Chapter 5.
Currently the CYP superfamily comprises, in all taxa, over 7000 genes classified
into 781 gene families. Of the 110 animal CYP families, 18 are found in vertebrates
( Nelson, 2008 ). The total number of functional CYP genes in any single mamma-
lian species is thought to range from 60 to 200 ( Gonzalez, 1990 ). In vertebrates, most
CYP families encode proteins involved primarily in specific endogenous functions
(i.e., steroid hormone biosynthesis and metabolism). Other families encode proteins
that appear to have more to do with the oxidation of exogenous compounds, such as