March 12, 1929 – August 23, 2015
PhD - University of Cambridge, 1955
Nitrosamine metabolism to active carcinogens and their role in causation of human cancer.
Methylamylnitrosamine (MNAN) produces esophageal cancer in rats. To explore this phenomenon, we are examining the metabolism of this nitrosamine by a cell fraction (the microsomes) from rat liver and esophagus, including the formation of hydroxy derivatives and aldehydes from the nitrosamine. Monoclonal antibodies that inhibit enzyme action and the pure enzymes are used to identify which particular cytochrome P450 enzyme is involved. We are also studying MNAN metabolism by microsomes from human esophagus and other human organs.
We are examining chemical reactions between amino acids and nitrite to form agents that could alkylate DNA, and analyzing human gastric juice for nitrosamines and related compounds. Compounds called "apparent total nitroso compounds" occur in gastric juice, feces and various foods. We are trying to separate and identify these compounds to see if they present a hazard. Current methods include HPLC on anion exchange columns, with assay by nitrosation of each fraction followed by analysis for apparent total nitroso compounds by NO liberation on treatment with HBr in boiling ethyl acetate. Fractions also are analyzed by preparation of trimethylsilyl derivatives followed by gas chromatography-mass spectrometry.
We also are examining the metabolism and mode of action of phenethyl isothiocyanate and diallyl sulfide, which are anticarcinogenic agents found in the cabbage family and in garlic, respectively. We especially are studying the fate of these compounds in the body and the reasons why they inhibit the induction of esophageal cancer by nitrosamines in rats.