Persistent defects in the hepatic monooxygenase system of adult rats exposed, perinatally, to maternally administered phenytoin.
Phenytoin is one of the most commonly used anticonvulsants in pregnant epileptic women. Unrelatedly, the drug is also an inducer of hepatic drug metabolizing enzymes. Considering these facts, we wanted to determine if maternal treatment with therapeutic-like doses for the rat of phenytoin would produce long-term defects in the metabolism and action of drugs in the dams' adult offspring. We found that peripartum exposure to phenytoin resulted in a significant depression in the maximal velocities of hepatic microsomal aminopyrine N-demethylase in the 28-day-old male and female offspring. When the animals were 4-to-5-month old adults, the maximal velocities for the demethylase and hexobarbital hydroxylase remained subnormal in the males but were elevated in the females exposed to the highest therapeutic-like dose of phenytoin. Hexobarbital-induced sleeping time measurements were in agreement with enzyme kinetic analyses. Lastly, the hepatic monooxygenases of the adult male and female rats exposed, perinatally, to all but the lowest dose of phenytoin, were much less responsive to the inductive effects of several low doses of phenobarbital. The results suggest that levels of phenytoin that may be therapeutic for the mother can produce defects in the developing hepatic monooxygenase system of the perinates, which can then permanently affect drug metabolism and action in adulthood. Furthermore, by disrupting the development of hepatic enzyme induction mechanisms, perinatal exposure to phenytoin may irreversibly alter an important homeostatic mechanism that is normally responsive to daily exposure to low levels of various endogenous and exogenous inducing agents.
D000633:Aminopyrine N-Demethylase / Q000378:metabolism*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D005260:Female; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D010672:Phenytoin / Q000008:administration & dosage* / Q000494:pharmacology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D011919:Rats, Inbred Strains; D012741:Sexual Maturation
D010672:Phenytoin; D006899:Mixed Function Oxygenases; C021352:hexobarbital hydroxylase; D000633:Aminopyrine N-Demethylase