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Received for publication October 4, 2005.
Revised December 6, 2005.
Accepted for publication December 7, 2005.
Although in vivo expression levels of the male-specific hepatic isoforms of P450 (CYP2C11, CYP2C13, CYP2A2 and CYP3A2) are determined by the episodic growth hormone profile secreted by male rats, these isoforms have been completely refractory to growth hormone regulation in hepatocyte culture. By using species specific rat growth hormone, at subphysiologic in vivo concentrations administered in two daily episodic pulses, we successfully induced CYP2C11 and CYP2A2 to near normal concentrations. Whereas inductive levels of CYP2C13 were subnormal, CYP3A2 was unresponsive to all hormonal treatments; quickly declining to undetectable concentrations. In agreement with in vivo findings, we observed that induction levels of the isoforms were always greatest when the male hepatocytes were exposed to the masculine-like episodic growth hormone profile, and least stimulated by the continuous feminine-like hormone profile. When administered alone, dexamethasone consistently increased isoform levels. However, when administered with growth hormone, the glucocorticoid was always antagonistic, suppressing growth hormone-induction of CYP2C11, CYP2C13 and CYP2A2. Lastly, the P450 isoforms were completely unresponsive to all treatments when the hepatocytes were derived from female rats supporting earlier findings that expression levels of sexually dimorphic P450 isoforms are inherently irreversible between sexes.
Key words:
CYP expression, CYP2A, CYP2C, cytochrome P450 isoforms, gender differences, hormonal regulation, sexual dimorphism
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