Early expression of requisite developmental growth hormone imprinted cytochromes P450 and dependent transcription factors

Abstract

The sexually dimorphic expression of cytochromes P450 (CYP) drug metabolizing enzymes has been reported in all species examined. These sex differences are initially expressed during puberty and are solely regulated by sex differences in the circulating growth hormone (GH) profiles. Once established, however, the different male- and female-dependent CYP isoforms are permanent and immutable, suggesting that adult CYP expression requires imprinting. Since the hormone that regulates an adult function is likely the same hormone that imprints the function, we selectively blocked GH secretion in some newborn male rats while others also received a concurrent physiologic replacement of rat GH. Rats were subsequently challenged, peripubertally, with either a masculine-like episodic GH regimen or the GH vehicle alone. The results demonstrate that episodic GH regulation of male-specific CYP2C11 and CYP3A2, as well as female-predominant CYP2C6, are dependent on developmental GH imprinting. Moreover, the induction and/or activation of major components in the signal transduction pathway regulating the expression of the principal CYP2C11 isoform is obligatorily dependent on perinatal GH imprinting without which CYP2C11 and drug metabolism would be permanently and profoundly suppressed. Since there are additional adult metabolic functions also regulated by GH, pediatric drug therapy that is known to disrupt GH secretion could unintentionally impair adult health.