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THE COUNCIL FOR TOBACCO REsLARCH-U.S.A.. INC. 900 Tl[IRD AVENUE NEW YORK, N. Y. 10022 DOXALD if. FORD. PH.D. AS9OClASE RESEARCH D1RECt0R Memorandum To: Dr. S.C. Sommers and Staff From: D.H.Ford Re: Site visit with Dr. H.L. Bra4 y WNt, Rockefeller University, NYC, N.Y, July 9. 1987. Grant No. 2016 entitled "Smoking and Estrogen Metabolism in Relation to Cancer Risk." Site visiters: D.H. Ford and H. McAllister. Goals: To determine why the putative risk for developing cancer in postmenapausal women smokers is roughly half the risk noted for non-smokers. Inasmuch as Dr. Bradlow has recently noted that there was a highly significant increase in the extent of estradiol-2-hydroxylation among premenapausal women smokers, leading to the formation of catechol-estrogens which have little peripheral estrogenic activity, he feels that smoking may enhance this depression of estrogenic activity and thus reduce the risk of developing endometrial cancer. He is also concerned as to whether or not the increase in 2-hydroxylation of estradiol is reversible, as might occur among women in a smoke-cessation program. The study of two other metabolic pathways involving estradiol, which might relate to the development of estrogen-dependent cancer will also be undertaken: 1. The aromatization of testosterone to estradiol (See Osawa, Grant No. 1643A, on the presence of an anti-aromatase in cigarette smoke) and 2. That of C-16ahydroxylation of estrogens.. Comment: Since this projest was only recently supported by CTR, our visit was more in the nature of an introduction of ourselves and to show interest in his program. His intitial studies with nicotine patches applied to male and female volunteers have not as yet indicated any specific changes in estradiol-2-hydroxylation which might be correlated with nicotine. This suggests to him that the increase in this metabolite in premenapausal smoking women may be due to some other component in smoke. Thus, at this time Dr. Bradlow is interested in undertaking a smoke exposure study with hamsters to determine if whole smoke will induce the anticipated changes in estradiol metabolism. To this end we discussed with him the relative merits of the Walton Horizontal Smoking apparatus as well as the smoke exposure equipment developed in Lexington, KY. If whole smoke should induce an increase in 2-hydroxylation, he feels the next step would be to utilize smoke condensates and then finally fractions of condensates, pretty much along the lines used by Osawa to determine that the anti-aromatase activity in smoke was caused by some of the nor-nicotine compounds present in smoke. A recent project being undertaken is to evaluate the 2-hydroxylation of estradiol in obese women, who appear to be at higher risk for endometrial cancer, who synthesize and release more estrogen than thinner women and who appear to

demonstrate a depression in the rate of estradiol 2-hydroxylation. Since smoking appears to have an effect on liver p450 enzymes (induction), is the increased risk for this cancer in obese women due to an effect at this level, or is it related to the increased storage of estradiol (via protection from degradation) in the increased number and volume of fat cells? Observation: It is obviously too early to judge the productivity obtained on this program from CTR support. However, Dr. Bradlow and his colleague, Dr. Michnovicz are enthusiastic and knowledgable in this area of research and appear to be truely intersted in how smoking might alter the biology of estradiol metaboism. However, they do not at this time profess an interest in an effect at the level of the anterior pituitary wherein, in rats, it has been demonstrated that whole smoke or nicotine depress the release of FSH and LH, which of itself might serve to reduce the levels of circulating estradiol and thus reduce the risk for developing endometrial cancer. At this time, however, this appears to be an interesting problem, likely to produce biologically useful results and worthy of continued CTR support DHF