Chemical Warfare - Organic Pollutants: An Ecotoxicological Perspective - page 9

majority of lipophilic xenobiotics be they naturally occurring or human-made (Lewis
1996; Chapter 2 of this topic). CYP gene families 1, 2, 3, and 4 are all involved in
xenobiotic metabolism. They have wide-ranging yet overlapping substrate specifici-
ties and, collectively, can detoxify nearly all lipophilic xenobiotics below a certain
size. Some of them are inducible, so they can be “upregulated” when there is expo-
sure to unduly high levels of xenobiotics.
The wide distribution of cytochrome P450 enzymes throughout all aerobic organ-
isms clearly indicates a prokaryotic origin with increasing diversification of forms
during the course of evolution of vertebrates. Attempts have been made to relate
the appearance of different forms of members of P450 families 1-4 to evolutionary
events, represented as an evolutionary tree originating from a primordial P450 gene
(Nelson and Strobel 1987; see Lewis 1996). Particular interest centers on the radia-
tion of the cytochrome P450 family 2 (CYP2; see Figure 1.2), which is believed to
have commenced about 400 million years ago, thus coinciding with the movement
of animals to land (Nebert and Gonzalez 1987). Whereas most aquatic organisms
can lose lipophilic compounds obtained in their food by diffusion across perme-
able membranes (especially respiratory membranes) into ambient water, this simple
detoxication mechanism is not available to terrestrial animals. They have evolved
detoxication systems (predominantly monooxygenases), which can convert lipophilic
compounds to water-soluble products that are readily excreted into urine and feces
(Chapter 2). Therefore, it seems reasonable to suggest that the radiation of CYP2
represents an adaptation of herbivorous/omnivorous animals to life on land, where
survival became dependent upon the ability to detoxify lipophilic toxins produced
by plants.

2.5

101

Prokaryotic

102

51
11

2.0

P450 gene

11A
11B

Eukaryotic

17
21

1.5 2E

2 2B

2

2D

1

3

4A1
4A4

1.0 4

0.5

0

0 200 400 600 800

Million Ye ars Ago

1000 1200 1400

fIgure 1.2 An abbreviated version of the P450 phylogenetic tree compared with an evo-
lutionary timescale (Lewis 1996). The dashed line represents a plot of evolutionary distance
(Nelson and Strobel 1987).