Forging the links between metabolism and carcinogenesis.
Metabolism plays important roles in chemical carcinogenesis, both good and bad. The process of carcinogen metabolism was first recognized in the first half of the twentieth century and developed extensively in the latter half. The activation of chemicals to reactive electrophiles that become covalently bound to DNA and protein was demonstrated by Miller and Miller [Cancer 47 (1981) 2327]. Today many of the DNA adducts formed by chemical carcinogens are known, and extensive information is available about pathways leading to the electrophilic intermediates. Some concepts about the stability and reactivity of electrophiles derived from carcinogens have changed over the years. Early work in the field demonstrated the ability of chemicals to modulate the metabolism of carcinogens, a phenomenon now described as enzyme induction. The cytochrome P450 enzymes play a prominent role in the metabolism of carcinogens, both in bioactivation and detoxication. The conjugating enzymes can also play both beneficial and detrimental roles. As an example of a case in which several enzymes affect the metabolism and carcinogenicity of a chemical, aflatoxin B1 (AFB1) research has revealed insight into the myriad of reaction chemistry that can occur even with a 1s half-life for a reactive electrophile. Further areas of investigation involve the consequences of enzyme variability in humans and include areas such as genomics, epidemiology, and chemoprevention.
Guengerich
F P
FP
Department of Biochemistry, Center of Molecular Toxicology, Vanderbilt University School of Medicine, 638 Medical Research Building I, 23rd Avenue South at Pierce, Nashville, TN 37232-0146, USA. guengerich@toxicology.mc.vanderbilt.edu
D016604:Aflatoxin B1 / Q000266:history / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000266:history* / Q000493:pharmacokinetics; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000266:history / Q000378:metabolism; D004247:DNA / Q000187:drug effects / Q000235:genetics / Q000266:history; D018736:DNA Adducts / Q000266:history; D004249:DNA Damage; D020022:Genetic Predisposition to Disease; D049673:History, 20th Century; D006801:Humans; D007527:Isoenzymes / Q000266:history / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology; D008967:Molecular Biology / Q000266:history; D016296:Mutagenesis; D009369:Neoplasms / Q000139:chemically induced / Q000266:history; D013329:Structure-Activity Relationship
D002273:Carcinogens; D018736:DNA Adducts; D007527:Isoenzymes; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1