Chemistry Reference
In-Depth Information
6.2.2 m
e T a b of l i s m
of f
pcb
s
In terrestrial vertebrates, the elimination of PCBs, similar to that of OC insecticides,
is largely dependent on metabolism. The rate of excretion of the unchanged congeners
is generally very slow, although it should be noted that small amounts are “excreted”
into milk (mammals) or eggs (birds, amphibians, reptiles, and insects), presumably
transported by lipoproteins (see Chapter 2). In mammals there can also be transport
across the placenta into the developing embryo. Although such “excretions” do not
usually account for a very large proportion of the body burden of PCBs, the translo-
cated congeners may still be in sufficient quantity to cause embryo toxicity.
In animals, primary metabolism of PCBs is predominantly by ring hydroxyla-
tion, mediated by different forms of cytochrome P450, to yield chlorophenols. The
position of attack is influenced by the location of substitutions by chlorine. As with
other lipophilic polychlorinated compounds, oxidative attack does not usually occur
directly on C-Cl positions; it tends to occur where there are adjacent unsubstituted
ortho-meta or meta-para positions on the aromatic ring. Unchlorinated para posi-
tions are particularly favored for hydroxylation, a mode of metabolism associated
with P450s of family 2 rather than P4501A1/1A2. In the case of aromatic hydroxyla-
tions, it has been suggested that primary attack is by an active form of oxygen gener-
ated by the heme nucleus of P450 (see Chapter 2) to form an unstable epoxide, which
then rearranges to a phenol (for further discussion of mechanism, see Trager 1988
and Crosby 1998). Two examples of hydroxylations of PCBs are shown in Figure 6.3:
one PCB is planar, the other coplanar.
Monooxygenase attack upon the coplanar PCB 3,3′,4,4′-tetrachlorobiphenyl
(3,3′4,4′-TCB) is believed to occur at unsubstituted ortho-meta (2′,3′) or meta-para
(3′,4′) positions, yielding one or other of the unstable epoxides (arene oxides) shown
in the figure. Rearrangement leads to the formation of monohydroxy metabolites.
In one case, a chlorine atom migrates from the para to the meta position during this
rearrangement (NIH shift), thus producing 4′ OH, 3,3′,4,5′-tetrachloro biphenyl. The
mechanism of formation of 2′OH, 3,4,3′,4′-TCB is unclear (Klasson-Wehler 1989).
In the rabbit, the nonplanar PCB 2,2′,5,5′-tetrachlorobiphenyl (2,2′,5,5′-TCB) is
converted into the 3′,4′-epoxide by monooxygenase attack on the meta-para position,
and rearrangement yields two monohydroxymetabolites with substitution in the meta
and para positions (Sundstrom et al. 1976). The epoxide is also transformed into a
dihydrodiol by epoxide hydrolase attack (see Chapter 2, Section 2.3.2.4). This latter
conversion is inhibited by 3,3,3-trichloropropene-1,2-oxide (TCPO), thus providing
strong confirmatory evidence for the formation of an unstable epoxide in the primary
oxidative attack (Forgue et al. 1980).
In the examples given, there is good evidence for the formation of an unstable
epoxide intermediate in the production of monohydroxymetabolites. However, there
is an ongoing debate about the possible operation of other mechanisms of primary
oxidative attack that do not involve epoxide formation, for example, in the produc-
tion of 2′OH 3,3′,4,4′-TCB (Figure 6.3). As mentioned earlier, P450s of gene family
1 (CYP 1) tend to be specific for planar substrates, including coplanar PCBs; they do
not appear to be involved in the metabolism of nonplanar PCBs. On the other hand,
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