Chemistry Reference
In-Depth Information
taBLe 2.5
Induction of enzymes other than monooxygenases
type of enzyme
Induced by
typical Substrates
Carboxylesterases
Phenobarbital, clofibrate,
aminopyrene
Carboxylesters
Epoxide hydrolases
Phenobarbital, trans stilbene
oxide, 2-acetyl aminofluorene
Epoxides
Glucuronyl transferases
Various, including phenobarbital
Many compounds with -OH groups
(and some with -SH groups)
Glutathione-
S
-transferases
Various, including phenobarbital
Wide range of electrophiles
dieldrin, can induce epoxide hydrolases. Finally, carboxyl esterases can be induced
by aminopyrene, phenobarbital, and clofibrate, but only to a limited extent (Hosokawa
et al. 1987). Generally speaking, these other inductions are of lower magnitude than
many inductions of the P450 system.
The inductions described here are believed to have evolved to protect animals
against plant and other naturally occurring toxins. However, when animals are
exposed to human-made xenobiotics, induction can have the opposite effect. Some
P450 forms can activate certain mutagens and insecticides, and induction of them
can lead to enhanced toxicity. Some of the pesticides developed by industry (e.g.,
phosphorothionate insecticides, see Chapter 10) depend on oxidative activation for
their efficacy. An interesting question is, to what extent, over the relatively short
period during which such compounds have been in use, have systems to counter the
production of active metabolites been evolved by species exposed to them (e.g., by
loss or downscaling of inducible P450 forms that are responsible for activation)? This
is relevant to the question of development of resistance by pests to pesticides, which
will be addressed in Chapter 4 and in Part 2 of this topic.
2.3.3
s
T o r a g e
A xenobiotic is said to be stored when it is not available to sites of metabolism or
action and is not available for excretion. In other words, it is held in an “inert” posi-
tion from a toxicological point of view, where it is not able to express toxic action or
to be acted upon by enzymes. A xenobiotic is stored when it is located in a fat depot
(adipose tissue), bound to an inert protein or other cellular macromolecule, or simply
held in a membrane that does not have any toxicological function (i.e., it does not
contain or represent a site of toxic action, neither does it contain enzymes that can
degrade the xenobiotic).
Highly lipophilic compounds such as organochlorine insecticides, PCBs, and
PCDDs tend to be stored in fat depots, where they can reach concentrations 10-50
times higher than in brain, liver, muscle, or other metabolically active tissues.
Although storage in fat can protect the organism in the short term, it may prove
damaging in the long term. Rapid mobilization of fat depots as a consequence of
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