Chemistry Reference
In-Depth Information
embryos (mammals). In a few cases (e.g., laying hens, which produce large numbers
of eggs), this can represent a significant mechanism of loss. In general, however, it
is not a sufficiently rapid mechanism to give much protection to the adult organ-
ism, although it constitutes a hazard to the next generation. Effective elimination
depends on biotransformation into water-soluble and readily excretable metabolites
and conjugates.
The metabolism of aldrin, dieldrin, endrin, and heptachlor in vertebrates is shown
in Figure 5.5. As with
p,p
′-DDT and related compounds, a high level of chlorination
greatly limits the possibility of metabolic attack by forming what is, in effect, a pro-
tective shield of halogen atoms. Monooxygenase attack might seem likely to be the
most effective and rapid mechanism of biotransformation for compounds such as these
which lack functional groups that are targets for more specialized enzymes (e.g., ester
groups, which are attacked by esterases). However, monooxygenases do not readily
attack C-Cl bonds—or, for that matter, C-Br or C-F bonds. Thus the most effective
attack tends to be on other positions on the molecule—for example, on the C=C of
the unchlorinated rings of aldrin and heptachlor, and on the endomethylene bridges
across the same in the cases of dieldrin and endrin (Figure 5.5; Brooks 1974, Walker
1975, Chipman and Walker 1979). The first type of oxidation yields stable epoxides
that are toxic and much more persistent than the parent compounds, and represents
activation, not detoxication. The second line of attack is a typical phase 1 detoxication,
yielding monohydroxy metabolites more polar than the parent compounds dieldrin
and endrin; moreover, such monohydroxy metabolites readily undergo conjugation to
form glucuronides and sulfates, which are usually rapidly excreted. The hydroxylation
of endrin occurs relatively rapidly because the endomethylene bridge is in an exposed
position for monooxygenase attack. It may be deduced that the molecule is bound to
one or more forms of P450 belonging to gene family 2, and that the endomethylene
group is thereby exposed to an activated form of oxygen generated from molecular
oxygen bound to heme iron (see Chapter 2). The endomethylene group of dieldrin is
less exposed than that of endrin, being screened by bulky neighboring chlorine atoms,
and metabolic detoxication is consequently a good deal slower (Hutson 1976, Chipman
and Walker 1979). Dieldrin is considerably more persistent in vertebrates than endrin
despite the fact that the two compounds are stereoisomers with very similar physical
properties, a logical consequence of the differential rates of metabolism. Thus, a ste-
reochemical difference between two compounds having the same empirical formula
may be reflected in large differences in toxicokinetics.
Cyclodiene epoxides such as dieldrin and heptachlor epoxide are also detoxi-
fied, albeit rather slowly, by epoxide hydrolase attack to form transdihydrodi-
ols (Figure 5.5). The diols are relatively polar compounds that may be excreted
unchanged, or as conjugates. There are very marked species differences in the abil-
ity to detoxify cyclodienes by epoxide hydrolase attack (Walker et al. 1978; Walker
1980). Using the readily biodegradable cyclodienes HEOM and HCE as substrates,
mammals showed much higher microsomal epoxide hydrolase activities than birds
or fish. Of the mammals, pigs and rabbits had particularly high epoxide hydrolase
activity, and it is noteworthy that the trans diol has been shown to be an important
in vivo metabolite of dieldrin in the rabbit, but not in the rat or the mouse, and not in
birds (Korte and Arent 1965, Walker 1980, Chipman and Walker 1979). In general,
Search WWH ::
Custom Search