106
Cytochrome P450
the requirement for testosterone at the
correct time during fetal life for the ap-
pearance of the male phenotype. Without
timely testosterone production, the 46,XY
male karyotype displays female sex char-
acteristics, and two different P450s (one
mitochondrial and one microsomal) are re-
quired for testosterone biosynthesis from
cholesterol. In the male songbird, testos-
terone produced in the testis crosses the
blood–brain barrier, where it is converted
to estrogen by the aromatase cytochrome
P450 in the brain, which activates the for-
mation of the song center in the brain.
Inherited genetic diseases are known to
be associated with mutations in the P450-
encoding genes involved in endogenous
substrate metabolism. For example, the
group of diseases known as congenital
adrenal hyperplasia results from defects
in steroid hormone biosynthesis in the
gonads and adrenal. Depending on the
speci±c
P450
gene affected, alterations
in these pathways lead to changes in
mineralocorticoid, glucocorticoids, or sex
hormone levels. Another P450-dependent
pathway subject to genetic defects is bile
acid biosynthesis. Recently, a mutation in
a fatty acid hydroxylase P450 expressed in
tubules in the kidneys has been found to
be associated with human hypertension.
Aromatase P450 is required for estrogen
biosynthesis and, in addition to expression
in the ovaries, it is found in adipose (fat)
tissue, in which it may be a key locus
in breast cancer. Thus, members of the
class of P450s involved in endogenous
substrate metabolism play important roles
in development and homeostasis and are
the loci for a number of disease states
in humans.
Forms of P450 involved in exogenous
substrate metabolism are generally more
widely distributed and have broader sub-
strate speci±cities than forms involved in
endogenous substrate metabolism. Exoge-
nous substrate metabolism is found in
every organ including the skin, while the
highest concentration and largest num-
ber of exogenous substrate–metabolizing
P450s is in the liver. Some forms in this
class are widely distributed, such as that
which metabolizes polycyclic aromatic hy-
drocarbons (P4501A1 – this nomenclature
is de±ned in the next section), which can
be found in almost every cell type. Others
are present in only a limited number of
cells such as the olfactory epithelium.
In bacteria, P450-dependent xenobiotic
(foreign compound) metabolism can in-
volve compounds that serve as important
carbon sources for these organisms. A par-
ticular strain of
Pseudomonas putida
grows
on camphor following its metabolism
via several enzymatic steps, including
one catalyzed by the soluble cytochrome
P450cam.
In
insects,
P450-dependent
xenobiotic metabolism can provide pro-
tection against plant toxins produced to
ward off pests. The larvae of the black
swallowtail butterfly are able to feed on
carrot and parsley plants because they can
rapidly induce a particular P450 that me-
tabolizes the xanthotoxin produced by the
plants. Many other insects cannot gener-
atesuchadefenseinthewarfarebetween
plants and insects and thus cannot feed
on naturally protected plants. Taxol, an
important anticancer agent that disrupts
microtubule formation, is produced by
the Paci±c yew tree via a P450-dependent
pathway as a defense against pests. An-
imals including humans contain a broad
spectrum of different P450s capable of bio-
transforming pollutants and drugs. These
transformations (generalized in Table 1)
involve countless drugs, chemical carcino-
gens, and environmental contaminants.
From an evolutionary point of view, it is
interesting to consider how these forms
previous page 1426 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 1428 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off