Ortiz de Montellano Paul R.(Ed.) Cytochrome P450. Structure, Mechanism, and Biochemistry
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Hormonal Regulation of Liver Cytochrome P450 Enzymes
365
during the pubertal period have depleted serum
androgen levels and a feminized pattern of hepatic
mRNA expression, as evidenced by a reduction in
CYP2C11,
CYP3A2, and CYP3A18 and by an
elevation in CYP2C12 and CYP3A9 (ref [232]).
However, the precise neuroendocrine mechanisms
responsible for the feminization of hepatic P450
enzyme expression by dietary zinc deficiency
remain to be elucidated.
Finally, caloric restriction and food deprivation
have been shown to modulate hepatic expression
of sex-dependent liver steroid-metabolizing
enzymes, including CYP2C11 (ref [233]) which is
suppressed, and CYP3A9 (ref [234]) and steroid
5a-reductase^^^, which are induced. These are sit-
uations in which glucagon levels are high and
insulin levels are low, analogous to the diabetic
state (see Section 5.3.1).
5.5. Impact on Drug Metabolism
and Procarcinogen
Activation
As discussed in Section 5.1, the anticancer
drug cisplatin provides an example of a foreign
chemical that depletes serum testosterone and
consequently feminizes the expression of liver
P450s in adult male rats. This type of alteration in
the profile of liver P450 enzymes could have
important pharmacological consequences, as sug-
gested by the finding that cisplatin suppression of
CYP2C11 decreases liver P450-catalyzed activa-
tion of anticancer prodrugs, such as cyclophos-
phamide^^^' ^^^' ^^^ and ifosfamide^^^ when
assayed in isolated microsomal systems. Liver
P450 activation of these latter two drugs is
required for their anticancer drug activity^^^, and
CYP2C11 contributes significantly to this meta-
bolic pathway in male rat liver^^^' ^^^. Clinical
studies indicate that cisplatin may exert effects
on circulating hormone levels in human cancer
patients that are similar, though not identical, to
those seen in rats^^^. If these hormone perturba-
tions in turn alter P450 enzyme levels in human
liver, this could have an impact on drug-drug
interactions in patients given cisplatin in combina-
tion with anticancer P450 prodrugs such as
cyclophosphamide.
As discussed
above,
drug metabolism in diabetic
rats can
be
altered as a consequence of perturbations
of GH secretory patterns and the resultant changes
in the expression of multiple liver P450 enzymes.
Accordingly, diabetes is associated with a decrease
in P450-mediated in vitro hepatic metabolism of
imipramine^^^'
^^^,
lidocaine^^^, codeine, and chlor-
promazine^^^. In addition, alteration of liver P450
expression in diabetes is postulated to be responsi-
ble for the enhanced in
vitro
metabolic activation of
certain chemical carcinogens, including Try-P-
1 (3-amino-1,4-dimethyl,5H-pyrido(4,5-b)indole)
and Try-P-2(3-amino-1 -methyl-5H-pyrido(4,3-b)
indole)^'*^ These examples demonstrate the poten-
tial for alterations in liver P450 expression that
potentially lead to reduced drug metabolism and
enhanced procarcinogen activation. Further investi-
gations will be necessary to determine the extent
to which these events occur in humans and to eval-
uate their true pharmacological and toxicological
significance.
6. Conclusion
Sex-dependent liver P450 enzymes are subject
to complex patterns and multiple mechanisms of
hormonal control. Plasma GH pulsatility, acting
via transcriptional mechanisms, is a key regulator
of liver-expressed, sex-dependent P450 enzymes
and their associated steroid hydroxylation and
xenobiotic metabolism activities. This results in
the sex differences in metabolism, pharmacoki-
netics,
and toxicity of various xenobiotics that are
seen in rodents and other species, including
humans. The pulsatile plasma GH profile charac-
teristic of adult male rats repeatedly stimulates
tyrosine phosphorylation that directly activates
the transcription factor STAT5b. This triggers
translocation of
STAT5b
into the nucleus, where it
is proposed to modulate transcription of sex-
dependent liver P450 genes through both direct
and indirect mechanisms. Continuous or near-
continuous exposure to GH, as occurs in the
female rodent liver, can downregulate liver
STAT5b signaling. As a consequence, active
nuclear STAT5b protein is generally found at a
low level in adult female rat liver. Thyroid hor-
mones are also important endocrine regulators of
liver metabolic function that can act directly, by
influencing the expression of individual P450
enzymes, as well as indirectly, via their effects on
NADPH-P450 reductase gene expression.
David J. Waxman and Thomas K.H. Chang
Gonadal hormones also play a role, but their
effects on liver P450 activity are largely indirect
and are mediated by the hypothalamic-pituitary
axis and its control of plasma GH levels. Sex
dif-
ferences in GH secretory dynamics also occur in
humans and can be modulated by gonadal hor-
mones. This sexually dimorphic GH secretion
may contribute to the apparent sex differences in
the levels of certain human P450s and in human
P450-catalyzed drug metabolism and pharmaco-
kinetics. Finally, diverse factors, including many
drugs and other xenochemicals, pathophysiologi-
cal state, and dietary factors can affect hormone
secretion and the hepatic expression of sex-
dependent P450s, which in turn may impact drug
metabolism and procarcinogen activation.
Acknowledgment
Studies carried out in the laboratory of DJW
were supported in part by the National Institutes
of Health (Grant DK33765).
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