112
Cytochrome P450
receptor transcription factor known as
SF-1, which also plays a key role in
organogenesis of the adrenal and gonads.
Constitutive regulation of steroid hydrox-
ylase levels is mediated by growth factors
and cytokines.
Many forms of P450 are induced by
substrates. Camphor, the substrate for
P450cam, regulates the level of this P450
and other enzymes involved in camphor
metabolism. It has been noted that xantho-
toxin produced by carrot and parsley plants
induces P450 levels in certain butterfly lar-
vae, permitting them to metabolize this
toxin and therefore feed on the plants.
Drugs and pollutants that serve as sub-
strates for many P450s can function to
induce the levels of the speci±c forms that
detoxify them. In a well-studied example,
polycyclic aromatic hydrocarbons, some of
which are substrates, induce the level of
P4501A1 through a speci±c receptor that
binds a unique DNA sequence associated
with CYP1A1 when the ligand (polycyclic
aromatic hydrocarbon) is bound. The same
regulatory process for P4501A1 exists in
±sh and all animals, raising the possi-
bility that there is an endogenous ligand
for this receptor. Polyacrylic aromatic hy-
drocarbons derived from burning organic
matter must have been in the environment
for a very long time. Modern polycyclics
such as dioxin are potent inducers of
this P450 by this receptor-mediated mech-
anism, which probably has existed for
millions of years. Therefore, the question
remains as to whether P4501A1 might be
regulated by a naturally occurring com-
pound that might also be a substrate for
this P450. Barbiturates such as pheno-
barbital enhance levels of certain forms
of drug-metabolizing P450s, while per-
oxisome proliferators such as clo±brate
induce levels of yet other P450s. Phar-
maceutical companies not only need to
know what forms of P450 metabolize po-
tential new drugs and what the resultant
metabolites are but they also need to
be aware of the forms of P450 that are
induced by such compounds, because al-
teration in the P450 pro±le by induction
can alter the pattern of drug metabolism.
Overall, the levels of P450s in all or-
ganisms are regulated by environmental
conditions. In higher organisms, develop-
mental, tissue-speci±c, and endogenous
systems also contribute to the existing
levels of P450s. Since there is little post-
translational modi±cation of P450s that
influences enzymatic activity, levels of the
monooxygenases themselves must be key
in controlling activity. Transcription is a
very important player in this aspect of P450
function, although translation that has not
been studied as extensively as transcription
may also be important.
6
Future Directions
This section, in 1996, began with three
questions that were considered to be
particularly important from the standpoint
of the pharmaceutical industry.
How many human forms of P450
are there?
From the human genome we now know
that there appear to be 57 human CYPs.
What are the overlapping substrate
speci±cities of the major P450 forms
to a variety of drugs?
Of course, this is a question that will for-
ever be an ongoing one because of the
development of new drugs. However,
we now know the number of CYPs and,
in most cases, they can be expressed
in heterologous systems providing suf-
±cient enzyme for analysis of substrate
speci±city. Thus, the methods are clearly
previous page 1432 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 1434 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off