Chemical carcinogenesis, mutagenesis, and teratogenesis.
An international symposium entitled Chemical Carcinogenesis, Mutagenesis and Teratogenesis: a Tribute to James and Elizabeth Miller was held in Toronto, Ont., July 19, 1994. This symposium theme was discussed in the presence of James Miller, 79 years young, who with his wife, Elizabeth Miller (1920-1987), are considered to be the pioneers of this medical and environmental toxicology research field. It is generally believed that the susceptibility of an individual to chemical carcinogenesis or teratogenesis varies considerably depending upon their genetic makeup, diet, lifestyle, and their environmental exposure. One goal of the research discussed at this symposium was an examination of the role of the enzymes involved in the metabolic activation and detoxification of carcinogens and teratogens. The interindividual variabilities in the levels and activity of these enzymes could contribute to the susceptibility of the individual to chemical carcinogens or teratogens. At the symposium evidence was presented indicating that theta-class glutathione (GSH) S-transferase levels activate dihalomethanes and could therefore initiate the carcinogenic response to butadiene and 1,2-dibromo-3-chloropropane. The dramatic genetic polymorphism of this class of GSH S-transferase could thereby contribute to the individual's susceptibility to these carcinogens. Similarly, the GSH S-transferase and GSH levels in the embryo and yolk sac that are determined during organogenesis could also be important factors in determining the susceptibility of the embryo to teratogens. The levels of cytochrome P450 1A2, aromatic amine N-acetyltransferases, and sulfotransferases could also determine 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 and 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 cytochrome P450s that activate the nitrosamines found in tobacco smoke suspected to cause lung cancer. Finally, the sulfotransferase isoforms involved in the metabolic activation of carcinogenic arylamines were identified.
O'Brien
P J
PJ
Faculty of Pharmacy, University of Toronto, ON, Canada. peter.obrien@utoronto.ca
Hales
B F
BF
Josephy
P D
PD
Castonguay
A
A
Yamazoe
Y
Y
Guengerich
F P
FP
D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D009153:Mutagens / Q000378:metabolism*
D002273:Carcinogens; D009153:Mutagens; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase