RT Journal Article
SR Electronic
T1 Ethanol-Mediated Transplacental Induction of CYP2E1 in Fetal Rat Liver
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1028
OP 1036
VO 282
IS 2
A1 Carpenter, Susan P.
A1 Savage, Daniel D.
A1 Schultz, Eric D.
A1 Raucy, Judy L.
YR 1997
UL http://jpet.aspetjournals.org/content/282/2/1028.abstract
AB We examined the potential for the widely consumed xenobiotic ethanol to transplacentally induce fetal rat CYP2E1. Throughout gestation, rat dams were fed a liquid diet containing 5% ethanol or two separate control diets. At 2 days before term, the dams were killed, and maternal and embryonic tissues were collected. Immunoblot analysis of microsomes from fetal liver, placenta and maternal brain revealed a band that comigrated with adult liver CYP2E1. The identity of the immunoreactive protein in placenta, brain and fetal liver was substantiated as CYP2E1 through restriction enzyme digestion of a reverse transcription-polymerase chain reaction product. Quantification of immunoblots containing microsomes from maternal and fetal liver of ethanol-treated dams displayed a 1.4- and 2.4-fold increase in CYP2E1, respectively, compared with microsomes from pair-fed controls. Chlorzoxazone and low substrate concentrations of N-nitrosodimethylamine were used as metabolic probes for CYP2E1. The rate of chlorzoxazone metabolism by maternal hepatic microsomes from dams fed the 5% ethanol diet was 2.6-fold greater than that of controls. Conversely, a negligible increase was observed in the rate of metabolism by hepatic microsomes from ethanol-exposed fetuses compared with pair-fed animals. When N-nitrosodimethylamine demethylation was examined, these same fetal samples exhibited greater rates of activity (1.5-fold) compared with microsomes from control animals. However, this increase was not as great as expected considering the 2.4-fold increase in CYP2E1 protein. Collectively, fetuses exposed to a 5% ethanol diet throughout gestation exhibited transplacental induction of an hepatic CYP2E1 that may possess different catalytic properties from the analogous adult enzyme. The American Society for Pharmacology and Experimental Therapeutics