Abstract
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,∼1:2) CYP2C7, exhibited a barbiturate-induced delayed, but persistent ∼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.
Footnotes
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Send reprint requests to: Bernard H. Shapiro, Laboratories of Biochemistry, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce St., Philadelphia, PA 19104-6048. E-mail:shapirob{at}vet.upenn.edu
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↵1 This study was supported by National Institutes of Health Grants HD16358 and GM45758.
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↵2 Current address: Department of Drug Metabolism, Merck Research Laboratories, P.O. Box 2000, RY80-A9, Rahway, NJ 07065-0900.
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↵3 The terms sex-dependent, sex-predominant or -dominant, and sex-specific are often used indiscriminately. We use sex- or gender-dependent to imply that expression levels are dependent on the existence of gender; sex- or gender-predominant indicates expression levels, regardless of magnitude, are consistently greater in one gender; and sex- or gender-specific implies that expression is basically restricted to only one gender.
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↵4 Although we have observed a persistent elevation of CYP2A2-dependent testosterone 15α-hydroxylase in male and female rats neonatally treated with phenobarbital, we have discounted the importance of any increased CYP2A2 in contributing significantly to the broadly overexpressed drug-metabolizing enzyme activities in the affected animals. In agreement with our finding of comparatively very low CYP2A2-testosterone 15α-hydroxylase activity in adult (150-day-old) male rat liver and virtually no activity in adult female liver (Fig. 3), CYP2A2 protein has been calculated to represent ∼1 to 2% of the total P450 in the male and basically nothing in the female (Thummel et al., 1988). Thus, even a permanent severalfold increase in the concentration of the isoform would make an almost irrelevant contribution, especially in the female, to the animals' hepatic monooxygenase activities.
- Abbreviation:
- CYP
- cytochrome P450
- Received December 28, 1999.
- Accepted February 17, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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