Synthetic Compounds Tamoxifen

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The anti-estrogen TAM has been widely used since 1971 for adjuvant therapy in the treatment of women with breast cancer. It is currently tested on a large scale as a chemopreventive agent in healthy women with a high familial risk for mammary tumors. In both breast cancer patients and healthy women treated with TAM, a small increase in the incidence of endometrial cancers was observed, as reviewed in [41]. In male and female rats, but not mice, TAM induced a high incidence of hepatocellular carcinomas. No uterine tumors were observed in adult rats or mice after treatment with TAM [41]. However, exposure of newborn CD-1 mice [42] and Wistar rats [43] to TAM during the first five postnatal days led to a significant increase in uterine tumors late in life.

In order to assess better the carcinogenic risk of TAM for humans, several laboratories are working on the mechanisms underlying the observed carcinogenic effects in rodents. There is general agreement that TAM acts as a genotoxic agent in the rat liver due to the formation of one or more reactive metabolites causing DNA adducts. TAM is metabolized via N-desmethylation, 4-hy-droxylation, a-hydroxylation, and N-oxidation in rat hepatic microsomes, rat hepatocytes, and in vivo [44]. a-Hydroxylation and 4-hydroxylation of TAM may represent the initial steps of metabolic activation (Fig. 5). For the genotox-icity of TAM in the rat liver, a-hydroxylation followed by sulfation appears to be

V0S03" a-sulfate-TAM

Fig. 5. Pathways proposed for the metabolic activation of tamoxifen the critical pathway leading to DNA adduction. The two major DNA adducts from the liver of TAM-treated rats were identified by mass spectrometry and comparison with authentic reference compounds [45,46] and are derived from the reaction of the exocyclic amino group of guanine with the a-position of TAM and N-demethyl-TAM (Fig. 6). 4-Hydroxy-TAM is not DNA reactive per se but can be oxidized to a quinone methide (Fig. 5), which reacts in vitro with DNA by a 1,8-Michael addition to yield (E)- and (Z)-a-(deoxyguanosin-N2-yl)-4-hydroxy-TAM (Fig. 6) as the major adducts. However, when 4-hydroxy-TAM was administered to rats or incubated with rat hepatocytes, no adducts could be detected in liver cell DNA by the 32P-postlabeling technique [47,48]. This sug-

Fig. 6. DNA adducts of tamoxifen detected in rat liver (left) and obtained from 4-hydroxy-TAM in vitro (right)

Fig. 6. DNA adducts of tamoxifen detected in rat liver (left) and obtained from 4-hydroxy-TAM in vitro (right)

gests that neither 4-hydroxy-TAM nor the product of subsequent hydroxylation, 3,4-dihydroxy-TAM (Fig. 5), play a significant role in the hepatocarcinogenicity of TAM in the rat.

Presently there are no epidemiological data suggesting that TAM is carcinogenic in the human liver. No TAM-specific DNA adducts were detected by 32P-postlabeling in liver biopsy samples of TAM-treated breast cancer patients [49], and incubation of human hepatocytes with TAM or a-hydroxy-TAM failed to yield significant levels of characteristic DNA adducts [50].

The etiology of the aforementioned endometrial cancer observed at low incidence in TAM-treated women is much less clear than that of TAM-induced rat liver cancer. Since previous attempts to detect DNA adducts in endometrial tissue failed or gave ambiguous results, a hormonal mechanism due to the partial estrogenic effect of TAM on the human uterus has been assumed. However, by using an ultrasensitive modification of the 32P-postlabeling technique, DNA adducts were recently detected in the endometrium of 6 out of 13 breast cancer patients but not in control subjects, and were identified as E- and Z-isomers of a-(N2-deoxyguanosinyl)-TAM [51], the same type of adduct as identified in rat liver (Fig. 6). The level of the endometrial adducts was in the range of 1-10 per 108 nucleotides, which is two orders of magnitude below the adduct level in rat liver at doses giving rise to tumors.

Why is TAM a potent genotoxic hepatocarcinogen in the rat and a poor geno-toxin, if at all, in humans, in spite of the fact that the critical metabolite, a-hy-droxy-TAM, is formed in both species? Studies by Glatt et al. [52] provide an explanation. Genetically engineered Salmonella typhimurium and Chinese hamster V79 cells, expressing various forms of rat and human sulfotransferases, were used to study the ability of a-hydroxy-TAM to induce DNA adduct formation and gene mutations in these cells. a-Hydroxy-TAM was mutagenic and gave rise to the same pattern of DNA adducts as observed in rat liver in vivo only in cells expressing rat hydroxysteroid sulfotransferase a, a liver-specific en zyme. Cells expressing the corresponding human sulfotransferase or six other human xenobiotic-metabolizing sulfotransferases, including the two sulfo-transferases identified in endometrium, were at least 20 times less active in metabolizing a-hydroxy-TAM to a genotoxin. This strongly suggests that the species difference between rat and mouse with respect to the genotoxicity of TAM resides in the different activities of a phase II enzyme, sulfotransferase, necessary to generate the ultimate carcinogen, i.e., the sulfate conjugate of a-hydroxy-TAM. The fact that the human liver and the human endometrium sul-fotransferases are not capable of activating a-hydroxy-TAM should provide some degree of protection.

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