CHEMICAL CARCINOGENESIS, MUTAGENESIS, AND TERATOGENESIS

An international symposium entitled Chemical Carcinogenesis, Mutagenes is and Teratogenesis: a Tribute to James and Elizabeth Miller was held in Toronto, Ont., July 19, 1994. This symposium theme was discussed i n the presence of James Miller, 79 years young, who with his wife, Eli zabeth Miller (1920-1987), are considered to be the pioneers of this m edical and environmental toxicology research field. It is generally be lieved that the susceptibility of an individual to chemical carcinogen esis or teratogenesis varies considerably depending upon their genetic makeup, diet, lifestyle, and their environmental exposure. One goal o f the research discussed at this symposium was an examination of the r ole of the enzymes involved in the metabolic activation and detoxifica tion of carcinogens and teratogens. The interindividual variabilities in the levels and activity of these enzymes could contribute to the su sceptibility of the individual to chemical carcinogens or teratogens. At the symposium evidence was presented indicating that B-class glutat hione (GSH) S-transferase levels activate dihalomethanes and could the refore initiate the carcinogenic response to butadiene and 1,2-dibromo -3-chloropropane. The dramatic genetic polymorphism of this class of G SH S-transferases could thereby contribute to the individual's suscept ibility to these carcinogens. Similarly, the GSH S-transferase and GSH levels in the embryo and yolk sac that are determined during organoge nesis could also be important factors in determining the susceptibilit y of the embryo to teratogens. The levels of cytochrome P450 1A2, arom atic amine N-acetyltransferases, and sulfotransferases could also dete rmine the susceptibility of the individual to carcinogenic arylamines. Accordingly, an Ames tester strain was described that was genetically engineered so as to express both aromatic amine N-acetyltransferase a nd human cytochrome P450 1A2. This should prove useful for predicting which arylamines are likely to be carcinogenic to humans. Nonsteroidal anti-inflammatory drugs may also prove useful in inhibiting the cytoc hrome P450s that activate the nitrosamines found in tobacco smoke susp ected to cause lung cancer. Finally, the sulfotransferase isoforms inv olved in the metabolic activation of carcinogenic arylamines were iden tified.