Phenobarbital-Imprinted Overinduction of Adult Constituent CYP Isoforms

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Abstract
Newborn male and female rats were treated with therapeutic-like levels of phenobarbital to determine whether early exposure to the barbiturate permanently alters (i.e., imprints) mechanisms regulating induction of constituent CYP (cytochrome P-450) isoforms. When the rats were 65 and 150 days old, they were rechallenged with phenobarbital at doses reflecting either the possible inducing activities of environmental agents (1 mg/kg) or at the minimal anticonvulsant therapeutic dose for the rat (10 mg/kg). The expression levels (mRNA and protein) of constituent, gender-dependent CYP2C6, CYP2C7, CYP2C11, CYP2C12, CYP2C13, and CYP3A2 and nonconstitutive CYP3A1 were monitored at various times (i.e., 0.1–136 h) during the rechallenge period. The major female-specific CYP2C12 and male-specific CYP2C13 were unresponsive to induction, whereas the major male-specific CYP2C11 responded to phenobarbital administration with a 100% increase in transcript levels that were not translated into new protein. The expression of the other isoforms was significantly elevated by both doses of phenobarbital (10 mg >1 mg), though CYP2C6, CYP3A1, and CYP3A2 levels were increased an additional 30–50% when the animals were neonatally exposed to the barbiturate, demonstrating for the first time that mechanisms regulating induction of constitutive CYPs in adults are imprintable at birth. This overinduction response appears to result, at least in part, from phenobarbital-programmed alterations in the sexually dimorphic plasma growth hormone profiles that normally regulate expression of the isoforms. The long-term health consequences of the overinduction response and possible clinical significance are discussed.