Stimulatory effect of cigarette smoking on the 15α-hydroxylation of estradiol by human term placenta

Abstract

Objective: Our objective was to characterize the oxidative metabolism of estradiol by human term placenta and its modulation by cigarette smoking. Methods: Placental microsomes were prepared from term placentas obtained from 13 cigarette smokers (20 to 30 cigarettes per day until the time of delivery) and 13 control subjects who were nonsmokers. Estrogen metabolism was studied by incubation of 250 nmol/L [3H]estradiol with placental microsomes and NADPH, and the estrogen metabolites were determined by HPLC and gas chromatography-mass spectrometry. Results: 2-Hydroxyestradiol was the major hydroxyestrogen detected, followed by 6α-hydroxyestradiol. Small amounts of several other hydroxyestrogen metabolites (4-hydroxyestradiol, 6β-hydroxyestradiol, 7α-hydroxyestradiol, and 16α-hydroxyestradiol) were also detected. Large amounts of estrone plus small amounts of 2-hydroxyestrone and unidentified nonpolar metabolites were formed. Cigarette smoking stimulated the placental hydroxylation of benzo[a]pyrene by about 16-fold. Cigarette smoking had little or no effect on the overall rate of placental estradiol metabolism or on the formation of estrone, 2-hydroxyestradiol, 2-hydroxyestrone, or 16α-hydroxyestradiol. However, placental formation of 4-hydroxyestradiol and 7α-hydroxyestradiol was increased 38% (P =.08) and 150% (P =.05), respectively, in cigarette smokers. The formation of 6α-hydroxyestradiol was decreased 33% (P =.04). Metabolic formation of 15α-hydroxyestradiol was observed during incubations of estradiol with placental microsomes from 11 of the 13 cigarette smokers, but this metabolite was not detected during incubations with placental microsomes from any of the 13 nonsmokers. Analysis of data from all 26 placentas showed that the 15α-hydroxylation of estradiol was highly correlated with benzo[a]pyrene hydroxylation (r = 0.93; P