Diallyl sulfide inhibits DES-induced DNA adducts in the breast of female ACI rats.

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Estrogen related cancer is the second leading cause of death in women. The biotransformation of estrogen is a critical factor in the initiation of estrogen-induced cancer. It has been demonstrated that diethylstilbestrol (DES), a stilbene estrogen, is biotransformed to reactive chemicals that produce DNA adducts. Diallyl sulfide (DAS), a potent chemopreventive compound found in garlic, has been shown to inhibit the biotransformtion of several procarcinogens such as benzo(a)pyrene and dimethylbenzsanthracine. We propose that DAS will prevent DES-induced breast cancer by inhibiting the metabolism of DES. To test this hypothesis, we investigated the ability of DES to produce DNA adducts in microsomal, mitochondrial, and nuclear in vitro metabolic systems and in vivo using female ACI rats. The ability of DAS to inhibit DNA adduct formation was also investigated. Microsomes, mitochondria, and nuclei were isolated from breast tissue of female ACI rats. These organelles were used to catalyze in vitro reactions containing DES and/or DAS. Five groups of five female ACI rats were treated via i.p. injections as follows: (1) control (corn oil), (2) 200 mg/kg DES, (3) 200 mg/kg of DAS, (4)200 mg/kg DES/200 mg/kg of DAS (5) 200 mg/kg DES /400 mg/kg DAS. The rats were sacrificed four hours after dosing. MtDNA and nDNA were isolated from the breast and analyzed by P³² post-labeling. In the in vitro reactions, we found that DES produced DNA adducts in all three systems. The relative adduct levels were 2.2 × 10⁻⁴, 6.2 × 10⁻⁶, and 2.9 × 10⁻⁷ in microsomal, mitochondrial, and nuclear reactions, respectively. DAS was able to inhibit DES-induced DNA adducts in all three systems. The percent inhibition ranged from 86% in the microsomes to 93% in the nuclei. In vivo results revealed that DES produced DNA adducts in both MtDNA and nDNA. DAS completely inhibited the DES-induced mtDNA adducts at 200 mg/kg. DAS caused a dose dependent decrease in the production of nDNA adducts. DES alone produced relative adduct levels of 2.92 × 10⁻⁷. DAS concentrations of 200 mg/kg and 400 mg/kg inhibited the DES induced DNA adducts by 71% and 85.3%, respectively. These findings suggest that DAS could inhibit DES-induced breast cancer by inhibiting its metabolism. Supported by Department of Defense Grant # DAMD 17-02-1-0381