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Metabolism. 1989 Jun;38(6):537-41.

Cigarette smoking alters hepatic estrogen metabolism in men: implications for atherosclerosis.

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Rockefeller University, New York, Health Foundation, Valhalla.


Studies of steroids and plasma lipoproteins in male cigarette smokers reveal that smoking is associated with an increase in peripheral estrogens and a decrease in high-density lipoprotein-cholesterol (HDL-C). We hypothesized that the lower HDL-C in this setting results in part from induction of the hepatic metabolic pathway that inactivates estrogen. This pathway, estradiol 2-hydroxylation, produces the peripherally inactive catechol estrogens 2-hydroxyesterone and 2-methoxyestrone. We used an in vivo radiometric method to assess 2-hydroxylation in 20 male smokers and 16 nonsmokers. The extent of the reaction (+/- SEM) was significantly higher among the smokers (43.3% +/- 1.9% v 24.6% +/- 1.9%, P less than .001). Smokers also excreted more urinary 2-hydroxyestrone (10.4 +/- 1.3 micrograms/g creatinine v 6.3 +/- 0.73 micrograms/g in nonsmokers, P = .011). The ratio of urinary 2-hydroxyestrone to estriol was higher on average among smokers (1.46 +/- 0.19 v 0.81 +/- 0.11, P = .006), and individual values correlated well with the radiometric test (r = .71, P less than .002). These data indicate that smoking is associated with significantly increased estrogen 2-hydroxylation in men. Preliminary evidence suggests that the smoking effect on C-2 hydroxylation may be opposed by ethanol. Elevated 2-hydroxylation in smokers, in the setting of modestly increased peripheral estrogens and a net decrease in HDLC, may be explained by the fact that lipoprotein synthesis and estrogen 2-hydroxylation both occur predominantly in the liver. Thus, greater metabolic inactivation of hepatic estrogens in male smokers could reduce HDLC, despite a modest rise in circulating hormone levels.

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