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Laboratories of Biochemistry, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104-6048
Address all correspondence and requests for reprints to: Dr. Bernard H. Shapiro, Laboratories of Biochemistry, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, Pennsylvania 19104-6048. E-mail: shapirob{at}vet.upenn.edu
Most of the constitutive hepatic P450 isoforms expressed in the rat
exhibit dramatic gender differences. Whereas only male hepatocytes
contain CYP2A2, 2C11, and 3A2, only female hepatocytes express CYP2C12
and 3- to 4-fold greater levels of CYP2C7. This sexually dimorphic
expression of hepatic P450 isoforms is regulated by the
gender-dependent secretory GH profiles, i.e. episodic in
males and continuous in females. In the case of the feminine GH
profile, the continuous presence of the hormone in the circulation
completely suppresses male-specific CYP2A2, 2C11, and 3A2, while
stimulating full expression of female-dependent CYP2A1, 2C7, 2C12, and
non-P450 testosterone 5
-reductase (type 1). The gender-dependent
expression of the P450s can be reversed by exposing male rats to the
continuous feminine plasma GH profile and females to the episodic
masculine GH profile. Under these conditions, females will now express
the male-specific isoforms and suppress the female-dependent forms,
whereas the opposite will occur in the males. Nevertheless, it is not
clear whether the levels of expression or suppression are comparable in
male and female rats exposed to the same sex-dependent GH profiles. In
the present study, we have renaturalized the circulating feminine GH
profile in euthyroid-maintained, hypophysectomized female and male rats
at six concentrations ranging from 3–100% of normal. Continuous
monitoring of GH levels revealed indistinguishable plasma profiles in
females and males at each dosage administered. In the case of females,
restoration of the feminine-like plasma GH profile at a concentration
that was 3% of the normal level restored expression levels
(i.e. mRNA, protein, and/or catalytic activity) of
female-dependent CYP2C12, 2A1, and 5-reductase to 50% or greater of
normal and fully suppressed expression of male-specific CYP2A2, 2C11,
and 3A2. Twice the dosage of the hormone (6% of normal) was required
to restore female-predominant CYP2C7 to 50% of normal in
hypophysectomized female rats. In contrast, we found that all of the
measured isoforms were significantly less responsive to the inductive
and suppressive effects of the feminine-like GH profile when
administered to male rats. While suppression of the male-specific
isoforms (i.e. CYP2A2, 2C11, and 3A2) in male rats
required concentrations of GH in the feminine profile 2–3 times
greater than were effective in female rats, no dosage of the hormone
was as effective in inducing female-dependent P450s
(i.e. CYP2A1, 2C7, and 2C12) in males as in females.
Clearly, the continuous feminine GH profile was more effective at
inducing and suppressing gender-dependent isoforms of hepatic P450
when restored to female rats, where it is normally secreted, than in
males. As GH profiles appear to be the sole factor responsible for
regulating the sexually dimorphic expression of hepatic P450 isoforms
in adult rats, the differential responsiveness of male and female rats
to the feminine GH profile are likely to be inherently induced by
irreversible imprinting during a critical developmental period.
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S. Nisar, C. S. Lane, A. F. Wilderspin, K. J. Welham, W. J. Griffiths, and L. H. Patterson A PROTEOMIC APPROACH TO THE IDENTIFICATION OF CYTOCHROME P450 ISOFORMS IN MALE AND FEMALE RAT LIVER BY NANOSCALE LIQUID CHROMATOGRAPHY-ELECTROSPRAY IONIZATION-TANDEM MASS SPECTROMETRY Drug Metab. Dispos., April 1, 2004; 32(4): 382 - 386. [Abstract] [Full Text] [PDF]
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A. K. Agrawal and B. H. Shapiro Constitutive and Inducible Hepatic Cytochrome P450 Isoforms in Senescent Male and Female Rats and Response to Low-Dose Phenobarbital Drug Metab. Dispos., May 1, 2003; 31(5): 612 - 619. [Abstract] [Full Text] [PDF]
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A. Kalsotra, S. Anakk, C. L. Boehme, and H. W. Strobel Sexual Dimorphism and Tissue Specificity in the Expression of CYP4F Forms in Sprague Dawley Rats Drug Metab. Dispos., September 1, 2002; 30(9): 1022 - 1028. [Abstract] [Full Text] [PDF]
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A. Kaufhold, P. K. Nigam, R. N. Dhir, and B. H. Shapiro Prevention of Latently Expressed CYP2C11, CYP3A2, and Growth Hormone Defects in Neonatally Monosodium Glutamate-Treated Male Rats by the N-Methyl-D-Aspartate Receptor Antagonist Dizocilpine Maleate J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 490 - 496. [Abstract] [Full Text] [PDF]
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R. N. Dhir, W. Dworakowski, and B. H. Shapiro Middle-Age Alterations in the Sexually Dimorphic Plasma Growth Hormone Profiles: Involvement of Growth Hormone-Releasing Factor and Effects on Cytochrome P450 Expression Drug Metab. Dispos., February 1, 2002; 30(2): 141 - 147. [Abstract] [Full Text] [PDF]
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M. C. Garcia, C. Thangavel, and B. H. Shapiro Epidermal Growth Factor Regulation of Female-Dependent CYP2A1 and CYP2C12 in Primary Rat Hepatocyte Culture Drug Metab. Dispos., February 1, 2001; 29(2): 111 - 120. [Abstract] [Full Text]
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N. A. Pampori, A. K. Agrawal, and B. H. Shapiro Infusion of Gender-Dependent Plasma Growth Hormone Profiles Into Intact Rats: Effects of Subcutaneous, Intraperitoneal, and Intravenous Routes of Rat and Human Growth Hormone on Endogenous Circulating Growth Hormone Profiles and Expression of Sexually Dimorphic Hepatic Cyp Isoforms Drug Metab. Dispos., January 1, 2001; 29(1): 8 - 16. [Abstract] [Full Text]
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A. K. Agrawal and B. H. Shapiro Latent Overexpression of Hepatic CYP2C7 in Adult Male and Female Rats Neonatally Exposed to Phenobarbital: A Developmental Profile of Gender-Dependent P450s J. Pharmacol. Exp. Ther., June 1, 2000; 293(3): 1027 - 1033. [Abstract] [Full Text]
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A. Yamada, M. Yamada, Y. Fujita, T. Nishigami, K. Nakasho, and K. Uematsu Self-augmentation Effect of Male-specific Products on Sexually Differentiated Progesterone Metabolism in Adult Male Rat Liver Microsomes J. Biol. Chem., February 9, 2001; 276(7): 4604 - 4610. [Abstract] [Full Text] [PDF]
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