Prenatal ethanol exposure induces dynamic changes of expression and activity of hepatic cytochrome P450 isoforms in male rat offspring

Abstract

This study aimed at determining the effect of prenatal ethanol exposure (PEE) on the expression and activity of cytochrome P450 (CYP) isozymes at different life stages of male rat offspring. Pregnant Wistar rats were administered with ethanol (4 g/kg/d) intragastrically from gestational day (GD) 9–20. Male offspring’s gene and activity of CYP isozymes were analyzed on GD 20 (only expression), postnatal day (PD) 84 and 196. Using aniline as probe, we compared the enzyme kinetics of hepatic CYP2E1 between two groups. Expression of CYP isozymes was examined in rat primary hepatocytes and human hepatic cell lines treated with ethanol or/and glucocorticoid. Gene level of Cyp1a2, 2b1, 2d1, 2e1, 3a1 and aryl hydrocarbon receptor were increased in PEE group on GD 20 and PD 84 and Cyp2e1 still exhibited an increasing trend on PD 196 compared with the control. PEE inhibited CYP2D1 and 2E1 activities in male offspring on PD 84. CYP activities in two groups became the same level on PD 196. PEE induced an opposite change in gene and protein level of hepatic CYP2E1 before and after birth. In consistent with lower protein level, aniline metabolism in PEE was weaker in liver microsome. Both single and combined use of ethanol or/and glucocorticoid increased CYPs expression in vitro. In conclusion, PEE programmed a higher gene and lower protein level of CYPs in male offspring, which dwindled with age. Impairment of protein levels and enzyme activities of CYPs may affect individual metabolism of endogenous and exogenous substances in early adulthood.