Biology Reference
In-Depth Information
that alachlor has a greater carcinogenic potential than metolachlor, the carcinogenic
responses to these compounds are species- and tissue-specific, alachlor being a nasal-
specific carcinogen in rats but not in mice. Metolachlor, on the other hand, is carci-
nogenic to the liver but not to nasal tissue (
U.S. Environmental Protection Agency,
1986, 1987
). Available evidence suggests that the species- and tissue-specific responses
observed, particularly for alachlor, result from specific metabolic enzymes, including
monooxygenases and arylamidases, and the generation of the putative carcinogenic
metabolite, diethylbenzoquinone imine (see
Coleman et al., 1999, 2000
, for appropri-
ate references).
The most studied generation of reactive metabolites from pesticides is the gener-
ation of oxons from organophosphorus compounds containing the P
S moiety by
oxidative desulfuration. Not only does this reaction produce the oxons, cholinesterase
inhibitors responsible for the neurotoxicity of these compounds, but it also releases
reactive sulfur, a potent CYP inhibitor (
Neal, 1980; Neal and Halpert, 1982; Neal
et al., 1983
); see Chapter 7 for further information on inhibition. The hepatic metab-
olism of organophosphorus insecticides continues to be investigated in both humans
and rodents. In general, through a common intermediate containing a phosphiithrane
ring, they are either activated to their oxons, potent inhibitors of acetylcholinesterase
and other esterases, or detoxified. This intermediate is generated by CYP isoforms, par-
ticularly CYP1A2; CYP2B6, and CYP 3A4 (see
Tables 5.1 and 5.3
).
The mode of action of the insecticide synergist piperonyl butoxide and other
methylenedioxyphenyl compounds is also due to a reactive metabolite, believed to be
a carbene derivative, that combines with the heme iron of CYP (
Dahl and Hodgson,
1979
; see Chapter 7).
PHYSIOLOGICAL FACTORS AFFECTING BIOTRANSFORMATION
Species, strains, and individuals may all vary in their susceptibility to toxicants, includ-
ing pesticides. In some cases it has been possible to explain these differences by one of
several causes, including differences in metabolism. In this section, some examples are
presented in which it is known that the activity of microsomal enzymes is influenced
by age, gender, and species.
Developmental Effects
Microsomal XME activity is low in the fetus and the newborn, but increases rapidly
during the early days or weeks of life (
Croom et al., 2009; Fouts and Adamson, 1959;
Ronis and Cunny, 1994, 2000
). For this reason fetuses and newborns are often more
susceptible to certain drugs and xenobiotics than adults. With aging, there is generally a
decrease in enzymatic activity, although increases in some activities have been observed
(
Kitahara et al., 1982; Van Bezooijen, 1984; Van Bezooijen et al., 1986
).
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