A chance observation that cigarette smoke interferes with the aromatase assay led us to investigate tobacco leaf and smoke extracts for the presence of aromatase inhibitors. The highest inhibitory activity was found in the basic fraction of cigarette smoke. Further purification of this fraction led to the identification of N-n-octanoylnornicotine. Synthesis and testing of a series of acylated nornicotines and anabasines for their ability to inhibit aromatase showed an interesting correlation of activity with the length of the acyl carbon chain, with maximum activity at C-11. The acylated derivatives showed activity which was significantly greater than that of nicotine and anabasine. In vivo studies in rats indicated that administration of this inhibitor delayed the onset of NMU-induced breast carcinoma and altered the estrus cycle. These in vivo studies suggest that tobacco alkaloid derivatives exert their effects by suppression of the aromatase enzyme system. Toxicity studies indicated relatively low toxicity with LD50 for N-n-octanoylnornicotine = 367 mg/kg body weight. When extracts from thirty five varieties of vegetables, plant leaves, and fruits were analyzed, seventeen showed quantitatively significant aromatase inhibition which was comparable to that of green tobacco leaf, suggesting that naturally occurring substances may affect endocrine function through aromatase inhibition.

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The effects of storage at -96 degrees C on the distribution of the total aromatase activity in the homogenate, 900 xg pellet and 900 xg supernatant of two human term placentas were studied. Both specific and total aromatase activities in the 900 xg pellet increased through storage at -96 degrees C, while that in the 900 xg supernatant decreased. The ratio of total aromatase activity between the 900 xg pellet and 900 xg supernatant was about 2:1 in fresh placenta, but the ratio was about 19:1 in placenta stored at -96 degrees C for 3.5 months. Total aromatase activity in the tissue homogenate remained fairly constant throughout five months of storage at -96 degrees C. These data indicate that although active microsomal aromatase is thought to be available only from fresh placenta and the activity is lost quickly during storage of the tissue, aromatase itself is stable for months at -96 degrees C and the 900 xg pellet prepared from the frozen tissue contains almost the total original aromatase activity in the fresh placental tissue.

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