Inhibition of gut glutathione transport by a breast cancer carcinogen

Abstract

Abstract Introduction: Oral intake of the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) causes breast cancer in the rat and is associated with a marked decrease in gut glutathione (GSH) efflux to the liver. We hypothesized GSH efflux is decreased by a block in either gut GSH production and/or GSH release leading to decreased liver detoxification of the carcinogen, facilitating adduct formation and carcinogenesis. Methods: GSH transport in jejunal basolateral membrane (JBLM) vesicles was investigated in female pubertal rats gavaged with 100 mg/kg DMBA (n = 15) or control (n = 15). Rats were pair-fed pre-defined chow and sacrificed one week post DMBA. Vesicles were prepared using Percoll differential centrifugation. Na+-dependent amino acid transport systems, A, ASC/B(0), and B(0,+) were examined using the inhibitors Me-AIB and Arginine. Transport velocity was determined by measuring 3H-GSH uptake. Blood and gut mucosal GSH were measured using spectrophotometric assay. Results: A significant decrease in Na+ dependent ASC/B(0) gut GSH transport velocity (42%) was seen in the DMBA group (21.89 +/− 2.63 pmol/mgprotein/min vs 35.52 +/− 4.05 pmol/mgprotein/min in controls, p Conclusions: One mechanism by which the carcinogen DMBA facilitates breast cancer induction may be through a significant decrease in gut GSH release secondary to an inhibition of the GSH ASC/B(0) transport system which would lead to increased DNA adduct formation and/or decreased carcinogen detoxification in the liver.