Cigarette smoking alters hepatic estrogen metabolism in men: implications for atherosclerosis.
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.
Michnovicz
J J
JJ
Rockefeller University, New York, Health Foundation, Valhalla.
Hershcopf
R J
RJ
Haley
N J
NJ
Bradlow
H L
HL
Fishman
J
J
D000328:Adult; D001161:Arteriosclerosis / Q000209:etiology*; D004964:Estriol / Q000652:urine; D004967:Estrogens / Q000378:metabolism* / Q000652:urine; D006801:Humans; D006894:Hydroxyestrones / Q000378:metabolism / Q000652:urine; D006900:Hydroxylation; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D012907:Smoking / Q000009:adverse effects*
D004967:Estrogens; D006894:Hydroxyestrones; D004964:Estriol; C003655:2-methoxyestrone; C024980:2-hydroxyestrone