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Chronic administration of tamoxifen to female rats causes hepatocellular carcinomas. We have investigated damage to liver DNA caused by the administration of tamoxifen to female Fischer F344/N rats or C57B1/6 or DBA/2 mice using 32P-postlabelling. Following the administration of tamoxifen for 7 days (45 mg/kg/day) and extraction of hepatic DNA, up to 7 radiolabelled adduct spots could be detected after PEI-cellulose chromatography of the 32P-labelled DNA digests. Tamoxifen caused a time-dependent increase in the level of adduct detected up to a value of at least 1 adduct/10(6) nucleotides after 7 days dosing. A dose response relationship was demonstrated over the range of 5-45 mg/kg/day (0.013-0.12 mmol/kg/day). On cessation of dosing there was a loss of adducts from the liver DNA. These adducts were not detected in DNA from vehicle-dosed controls or in DNA from kidney, lung, spleen, uterus or peripheral lymphocytes. Pyrrolidinotamoxifen caused a similar level of adduct formation as tamoxifen. In contrast, no significant adduct formation could be detected in liver DNA from rats given droloxifene or toremifene. Mice given tamoxifen (45 mg/kg/day for 4 days) showed levels of adducts in the liver which were 30-40% of those present in rats. Exposure of rat hepatocytes to tamoxifen in vitro, resulted in induction of unscheduled DNA synthesis, when preparations from rats which had been pretreated with tamoxifen in vivo were used. No such increase could be detected in hepatocytes from control rats, suggesting tamoxifen may induce enzymes responsible for its own activation. Tamoxifen induced a significant increase in micronucleus formation in a dose dependent manner in cultures of MCL-5 cells, a human cell line that expresses 5 different human cytochrome P450 isoenzymes, as well as epoxide hydrolase.

Lung cancer is the most common cancer in men in the United Kingdom and the second most common in women, accounting for between 25 and 40% of all cancer deaths. Cigarette smoking is widely accepted as the major cause of lung cancer and linear relationships have been established between the number of cigarettes smoked and lung cancer risk. Although approximately 50 carcinogenic chemicals have been identified in cigarette smoke, a causal link between specific compounds and lung cancer has yet to be made. Studies on cigarette smokers' urine, blood and placenta have provided indications of carcinogen exposure, and although the presence of covalently-bound adducts in human DNA provides evidence of exposure to carcinogens, there have been no reports of systematic studies on the levels of DNA adducts in human lung. We report here, using the 32P-post-labelling technique, that cigarette smokers have higher adduct levels than non-smokers, that there is a linear relationship between adduct levels and daily or lifetime cigarette consumption, and that people who have given up smoking for at least five years have adduct levels similar to those of non-smokers.

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