Latent overexpression of hepatic CYP2C7 in adult male and female rats neonatally exposed to phenobarbital: a developmental profile of gender-dependent P450s.
For more than 20 years it has been known that neonatal exposure to phenobarbital results in a delayed, but permanent overexpression of drug-metabolizing enzymes in adult male and female rats. Accordingly, to identify the specific isoform(s) of P450 responsible for the imprinted overexpression of hepatic monooxygenases, we have monitored the developmental profile of some dozen hepatic P450 isoforms in 4- to 150-day-old male and female rats neonatally treated with the barbiturate. Some of the cytochrome P450s (CYP), i. e., CYP2A1, 2A2, 2C6, 3A1, and 3A2, exhibit the typical transient response in which isoform levels (mRNA, protein, and/or specific catalytic activity) rise precipitously at the time of phenobarbital administration and rapidly decline to preinduction levels after withdrawal of the barbiturate. Other isoforms, i.e., CYP1A1, 1A2, 2C7, 2C11, 2C12, and 2C13, were neither constitutively expressed nor phenobarbital inducible in the neonate. Only one of these isoforms, female predominant (M:F, approximately 1:2) CYP2C7, exhibited a barbiturate-induced delayed, but persistent approximately 30 to 50% overexpression from puberty through adulthood. We propose that at the time of exposure, neonatally administered phenobarbital produces a "silent" programming defect resulting in a delayed, but persistent overexpression of the isoform, contributing, at least in part, to a permanent elevation of hepatic drug-metabolizing enzyme activities.
Agrawal
A K
AK
University of Pennsylvania School of Veterinary Medicine, Philadelphia 19104-6048, USA.
Shapiro
B H
BH
D000367:Age Factors; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D007527:Isoenzymes / Q000096:biosynthesis*; D008099:Liver / Q000201:enzymology*; D008297:Male; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D010634:Phenobarbital / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics
D007527:Isoenzymes; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; C021352:hexobarbital hydroxylase; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D039181:Steroid 16-alpha-Hydroxylase; D010634:Phenobarbital