Biotransformation (Metabolism) of Pesticides - Pesticide Biotransformation and Disposition - page 91

Skin
Because the skin is the largest organ in the human body, is continuous over the surface
area of the body, and is in direct contact with the environment, it is often the portal
of entry for pesticides and other xenobiotics. The skin is known to contain many of
the XMEs found in the liver, and some of these have been shown to be inducible,
primarily by polycyclic hydrocarbons ( Goerz et al., 1994; Jugert et al., 1994; Baron
et al., 2008 ). The metabolic capacity of skin for pesticides was shown early when slices
of rabbit skin were shown to hydrolyze paraoxon at a concentration of 7.7  10  3 M
to the extent of 20% in 1 h/g of tissue. Because the absorption of paraoxon and
related compounds is slow, this metabolism may be an important defense mechanism
( Fredriksson et al., 1961 ). By use of in vitro methods, such as the isolated perfused
porcine skin flap ( Carver et al., 1990 ) and mouse skin microsomes ( Venkatesh et al.,
1992a ), the skin has been shown to have the capacity to metabolize a variety of pes-
ticides. For example, Chang et al. (1994) , using the isolated perfused porcine skin flap,
showed that both carbaryl and parathion were metabolized during uptake by the skin.
Kidney
Because of the kidney's high blood flow, its ability to concentrate chemicals, and the pres-
ence of renal XMEs, the kidney may also be a site of toxicity from xenobiotics. Many of
these toxic effects can be directly attributable to the presence and localization of specific
forms of enzymes responsible for activation ( Hu et al., 1993; Speerschneider and Dekant,
1995 ). Several studies have highlighted the importance of renal oxidative enzymes, par-
ticularly FMO, in the metabolism of pesticides and other xenobiotics ( Kinsler et al., 1988;
Tynes and Hodgson, 1983 ). As was the case with the lung, the renal FMO enzymes
played a greater role in microsomal systems in the oxidation of several pesticides than
renal CYP, suggesting an important role for FMO in the extrahepatic metabolism of tox-
icants. Studies of kidney FMO have provided evidence for several isoforms in the kidney,
including the forms found in liver and lung ( Atta-Asafo-Adjei et al., 1993; Burnett et al.,
1994; Ripp et al., 1999; Venkatesh et al., 1991 ), and Furnes and Schlenk (2005) have
demonstrated the sulfoxidation of fenthion and methiocarb by kidney FMO.
Central Nervous System
Very little is known about XMEs in the central nervous system (CNS). Several studies
have demonstrated CYP activity and constitutive expression of various CYP isozymes
( Britto and Wedlund, 1992; Ghersi-Egea et al., 1993; Hansson et al., 1992; Hodgson
et al., 1993; Miksys and Tyndale, 2009 ). The activation or detoxication of pesticides by
the CNS is of particular interest in the case of pesticides that both exhibit their action
and are metabolized in the brain. Studies by Chambers and Chambers (1989) demon-
strated that the neurotoxicity of a series of organophosphorus compounds correlated
better with their activation in the brain than with activation in the liver.