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the capacity to activate and deactivate pesticides and other xenobiotics. Early studies
showed that parathion is metabolized to paraoxon and diethylphosphorothioic acid by
rabbit lung at about 20% of the rate in liver ( Neal, 1972 ).
Several studies have demonstrated the importance of pulmonary CYP and FMO
enzymes in pesticide oxidation ( Feng et al., 1990; Li et al., 1992 ). In the lung, FMO
appears to play a more important role than CYP in the oxidation of certain pesticides
and xenobiotics ( Kinsler et al., 1988; Tynes and Hodgson, 1983, 1985a,b ). Other stud-
ies have shown the existence of an FMO form now known as FMO2 in the lung
that is not present in the liver ( Lawton et al., 1990; Tynes and Hodgson, 1983; Tynes
et al., 1985; Venkatesh et al., 1992b; Williams et al., 1984, 1985 ). Boland et al. (2004)
demonstrated the metabolism of naphthalene, primarily to the dihydrodiol, in respira-
tory tissues of rhesus monkeys, and the metabolism and toxic effects of naphthalene in
respiratory tissues continues to be of interest ( Bogen et al., 2008 ).
Nasal Tissues
The nasal mucosa is the first tissue of contact for inhaled xenobiotics and compounds
have been identified that cause nasal lesions or tumors in experimental animals.
The drug-metabolizing activity of nasal tissues has been reviewed by Reed (1993)
and, more recently, by Ding and Kamienski (2003) . Enzymes known to be present
include a variety of CYPs (CYP1A1, 2B1, 2E1, 3A1, 4A1, 2G1), FMOs, carboxylester-
ases, epoxide hydrolases, glutathione S -transferases, and UDP-glucuronyl transferases.
It is of some interest that, despite the low concentrations of nasal CYP enzymes, these
have been demonstrated to have greater specific activity toward several substrates than
liver CYPs, perhaps as a result of higher ratios of NADPH cytochrome P450 reductase
to CYP in the nasal tissues. Nasal CYPs appear to be less inducible than liver isoforms,
although they appear to be sensitive to a number of CYP inhibitors.
Few pesticides are known to give rise to toxic endpoints in the nasal tissues.
However, alachlor, a restricted-use chloroacetamide herbicide that at one time was
widely used in agriculture, was demonstrated to cause rare nasal carcinomas in rats.
The putative metabolic product thought to be responsible for its carcinogenicity was
identified as diethylbenzoquinoneimine (DEBQI), which is produced only after exten-
sive metabolism of alachlor, involving CYPs as well as an aryl amidase. Human CYP
isoforms 2B6 and 3A4 are among those that have been identified as being important in
the production of metabolite precursors to DEBQI ( Coleman et al., 1999, 2000 ).
Genter and co-workers ( Deamer et al., 1994; Genter et al., 1995, 1998 ) have dem-
onstrated the role of microsomal epoxide hydrolase and CYP2E1 in the nasal toxicity
of dichlobenil in the mouse. It was subsequently shown that CYP2A10 and 2A11, iso-
forms that comprise some 25% of the total olfactory CYP content, also play an impor-
tant role in the nasal toxicity of dichlobenil ( Ding et al., 1994, 1996 ).
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