Factors Determining the Toxicity of Organic Pollutants to Animals and Plants - Organic Pollutants: An Ecotoxicological Perspective - page 42

absence of oxygen, electrons can be passed from the iron atom of heme to the sub-
strate. In the case of organohalogen compounds such as p,p ′-DDT, carbon tetrachlo-
ride, and halothane, this leads to the loss of Cl − and its replacement by hydrogen. If
oxygen had been present, the electron would have passed to this (see Figure 2.4) and
not directly to the substrate. With nitroaromatic compounds, reductions occur via an
intermediate hydroxylamine stage to yield an amine (Figure 2.13). Often, the second
stage is rapid, and the intermediate form is not detectable.
Although the role of P450 in this type of reductive metabolism has been well
established in in vitro studies, there are uncertainties about the course of events
in vivo. In the first place, as mentioned earlier, oxygen levels may be high enough
to prevent the occurrence of this type of reaction (see discussion about the metab-
olism of p,p ′-DDT in Chapter 5). Also, porphyrins other than P450 can catalyze
reduction. So, too, can flavoprotein reductases such as NADPH or cytochrome P450
reductase. Even FAD can catalyze some reductions. Microorganisms in anaerobic
soils and sediments can be very effective in degrading organohalogen compounds
such as organochlorine insecticides, PCBs, and dioxins. The metabolic degradation
of polyhalogenated compounds is often difficult and slow under aerobic conditions.
Effective aerobic detoxication enzymes have yet to evolve for many compounds of
this type. On the other hand, reductive dehalogenation is often an effective mecha-
nism for biodegradation and has been exploited in the development of genetically
manipulated microorganisms for bioremediation.
The transfer of electrons in xenobiotic reactions is tied up with the problem of the
generation of active radicals, including those of oxygen. CCl 4 , for example, is reduced
to the highly reactive CCl ∙ radical. Some organonitrocompounds, like the herbicide
paraquat, can undergo redox cycling. One electron reduction of the paraquat yields
an unstable radical. This radical passes an electron on to molecular oxygen, thereby
generating the reactive superoxide ion and regenerating paraquat (see Chapter 13).
2.3.2.6 conjugases
Conjugases catalyze phase 2 biotransformations, the coupling of xenobiotic metabo-
lites (and sometimes original xenobiotics), with polar endogenous molecules, which
are usually in the form of anions. Although phase 1 biotransformations of lipo-
philic compounds occur predominantly in the endoplasmic reticulum (“microsomal
membrane”), phase 2 biotransformations often occur in the cytosol. Many different
endogenous molecules are utilized for conjugation, and there can be large differences
between groups and between species, in the preferred metabolic pathway. The critical
thing is that polar conjugates are produced that can be rapidly excreted. The following
account will be mainly concerned with three groups of enzymes that are responsible
for most of the conjugations in vertebrates: glucuronyl transferases, sulfotransferases,
and glutathione- S -transferases. It should be emphasized that less is known about the
conjugases of invertebrates and plants. Although conjugations are seen to be detoxi-
fying, and in general protective toward the organism, in some instances conjugates
are broken down to release potentially toxic compounds. For example, some glutathi-
one conjugates can break down in the kidney, with toxic effects.
UDP-Glucuronyl transferases (henceforward simply glucuronyl transferases )
exist in a number of different forms with contrasting, yet overlapping, substrate