Principles of covalent binding of reactive metabolites and examples of activation of bis-electrophiles by conjugation.
Mechanisms of toxicity continue to be important in developing rational strategies to deal with chemicals present in the environment. Understanding and predicting toxicity have also become a critical step in the process of drug development. Covalent binding of chemicals to macromolecules is one aspect of toxicity, and the principles and outcomes of the process are considered. Two examples of chemicals for which several aspects of metabolism and reactions are understood are aflatoxin B(1) and polyhalogenated olefins. Ethylene dibromide is a compound that is activated to genotoxic half-mustards by conjugation with glutathione or the DNA repair protein O(6)-alkylguanine DNA alkyltransferase (AGT). The AGT reaction is unusual, in that crosslinking of the protein to DNA increases mutagenicity. One of the involved mechanisms is formation of N(7)-guanyl crosslinks and depurination to produce G-->T transversions; other reactions appear to yield the additional mutagenic events. The phenomenon of thiol conjugation to increase mutagenicity is widespread among bis-electrophiles.
Guengerich
F Peter
FP
Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, 638 Robinson Research Building, 23(rd) and Pierce Avenues, Nashville, TN 37232-0146, USA. f.guengerich@vanderbilt.edu <f.guengerich@vanderbilt.edu>
D016604:Aflatoxin B1 / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001711:Biotransformation; D002070:Butadienes / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D003432:Cross-Linking Reagents / Q000737:chemistry; D004247:DNA; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D004249:DNA Damage; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D015946:Ethylene Dibromide / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D005544:Forecasting; D005798:Genes, Bacterial; D005978:Glutathione / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D008239:Lysine / Q000378:metabolism; D008956:Models, Chemical; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009153:Mutagens / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D009154:Mutation; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D010084:Oxidation-Reduction; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction; D013750:Tetrachloroethylene / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D014241:Trichloroethylene / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity
D002070:Butadienes; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D009153:Mutagens; D015946:Ethylene Dibromide; D014241:Trichloroethylene; D004247:DNA; D016604:Aflatoxin B1; D019853:O(6)-Methylguanine-DNA Methyltransferase; D005978:Glutathione; C031763:1,3-butadiene; D008239:Lysine; D013750:Tetrachloroethylene