METABOLIC CONVERSIONS OF AROMATIC AMINES &PATHOGENESIS OF BLADDER CANCER

Washington University, Saint Louis MO

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Abstract

Aromatic amines, such as benzidine, are thought to induce bladder cancer via pathways involving metabolic activation to reactive species that result in modification of DNA. Over the last five years we have developed a model of benzidine-induced bladder cancer that has depended heavily on identification and quantitation of benzidine metabolites and synthetic standards at the Washington University Mass Spectrometry facility using GC/MS, FAB/MS, high resolution MS, and ESI/MS/MS. Our model is that, in human liver, benzidine is first N-acetylated and then converted to an N/-glucuronide, which is then excreted in urine. In acidic urine, the glucuronide is hydrolyzed to N-acetylbenzidine, which accumulates in bladder epithelial cells and is converted to reactive species by the peroxidase activity of prostaglandin H synthase. These species then form adducts, including N'-(3'-monophospho-deoxyguanosin-8-yl)-N-acetylbenzidine (dGp-ABZ), that cause mutations that initiate ca rcinogenes is. Developing and testing various aspects of this model have required mass spectrometric characterization of the intermediates proposed to be involved in this pathway.