Cytochrome P450
113
available to test the ability of different
human CYPs to metabolize a common
substrate. Most often, this analysis will
not include all 57 human CYPs but
rather the 6 major drug-metabolizing
forms in human liver (3A4, 2C9, 2C19,
2E1, 2A1, 2D6).
How are the major human forms of
P450 regulated?
This has been a rapidly growing area
of research over the past seven years.
Particularly, discovery of transcription
fac
torssuchasPXR
,CAR
,LXR
,a
long
with further understanding of the mech-
anism by which AhR functions to in-
duce CYPs through polycyclic aromatic
hydrocarbons, have begun to bring ra-
tionale answers to this question.
The other two questions in 1996 are
What genetic and environmental factors
control the individual levels of these en-
zymes, and can noninvasive screening
tests be developed to determine an indi-
vidual’s P450 proFle?
Can designer drugs be developed for
targeting speciFc P450 active sites?
We do not have clear answers to these
at this time. However, development of
microarray technologies and methods for
solving the structures of human CYPs
should assure some answers to these
questions by the time the next volume
is written. Many of the same questions
are also being asked by the agricultural
industry in its search for new herbicides
and pesticides.
The role of the P450 superfamily in
growth and development will be one of the
major issues addressed in academic labo-
ratories during the next decade, along with
the elucidation of the three-dimensional
structure of eukaryotic P450s and the
biochemistry of the regulation of
P450
gene expression. In addition, questions
that remain to be answered focus on
substrate accessibility and binding, par-
ticularly to P450s of the endoplasmic
reticulum, and association of these P450s
with limiting amounts of P450 reductase
in the membrane.
One of the major thrusts during this
decade will be in application of the unique
chemistry catalyzed by P450s for com-
mercial purposes. The recent success in
producing cortisol by insertion of a mam-
malian P450–dependent metabolic path-
way in yeast is very exciting and opens the
door to other future efforts. At the same
time, the solution of the
Streptomyces coeli-
color
genome demonstrating the presence
of 18
CYP
genes opens the way to modiF-
cation of P450s leading to novel secondary
metabolites. The opportunity will soon
exist to make novel and more potent an-
tibiotics by modifying speciFc
CYP
gene(s)
in particular streptomycetes. The use of
microorganisms for expression of speciFc
forms of P450 may also prove important in
pollutant control. Organisms engineered
to metabolize compounds such as poly-
cyclic aromatic hydrocarbons may be very
important in protecting the environment.
In the context of Fne chemical or pharma-
ceutical synthesis and in pollution control,
the ability to change the catalytic activity
of a speciFc P450 could be particularly
useful. The realization of designer P450s
engineered to catalyze speciFc activities
may not be far in the future, since solution
of the three-dimensional structure of eu-
karyotic P450s would seem to be a lesser
obstacle than before.
±inally, transgenic plants expressing
P450s that provide protection against
insects and herbicides are presently being
tested. Also, transgenic plants are being
developed to modify flower color and for
the production of commercially important
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