Effect of 7,12-dimethylbenz[a]anthracene (DMBA) on Gut Glutathione Metabolism

Background: One mechanism of the mammary carcinogenesis of 7,12-dimethylbenz[a]anthracene (DMBA) is thought to be the generation of reactive oxygen species known to play an important role in initiation and progression. We hypothesized that DMBA would disrupt gut glutathione (GSH) metabolism and this disruption would correlate with mammary cell carcinogenesis.

Methods: Sixty-four Sprague-Dawley rats were randomized to the DMBA versus control groups. At age 50 days, rats were gavaged with a one-time dose of 20 mg DMBA or sesame oil. Rats from each group were sacrificed at 1 week (n = 16), 2 weeks (n = 16), 4 weeks (n = 16), and 11 weeks (n = 16). Tumor appearance, arterial and gut GSH concentration, and gut GSH extraction were measured over time.

Results: Gut GSH extraction (normally negative; production) was significantly depressed over the time points, even showing uptake (positive extraction) at Weeks 1 and 2. Tumors developed in all animals in the DMBA group by Week 11.

Conclusions: A one-time oral administration of DMBA has a significant and prolonged depressive effect on gut GSH production that has not previously been described. These data support the hypothesis that the carcinogenic effect of DMBA is mediated, at least in part, by oxidative damage and that the disruption of gut GSH metabolism may play a greater role in carcinogenesis than previously realized.