Molecular toxicology and the medicinal chemist.
Drug metabolism has a number of pharmacodynamic and pharmacokinetic consequences which cannot be ignored even at the early stages of drug research. A number of aspects of drug metabolism are thus of interest to medicinal chemists, e.g. prodrug and soft drug design. This mini-review focuses mainly on toxication resulting from reactions of functionalization and conjugation. In the former case, oxidoreductases can reduce xenobiotics to nucleophilic radicals, or oxidize them to electrophilic and oxidizable metabolites. Conjugation reactions also play a role in toxication by generating lipophilic residues (e.g. hybrid triglycerides) or adduct-forming metabolites (e.g. some acylglucuronides), or by interfering with physiological pathways (e.g. Coenzyme A conjugates). Functional moieties undergoing such reactions are known as toxophoric groups. Because they are the biochemical endpoint of several toxication reactions, macromolecular adducts are now of special significance in molecular toxicology. But, as discussed in the conclusion, the substrate specificity of drug-metabolizing enzymes, the many biological factors that influence metabolism, and various repair and removal mechanisms all contribute to decrease toxicological risks and to protect organisms.
Testa
B
B
Institut de Chimie Thérapeutique, Ecole de Pharmacie, Université de Lausanne, Switzerland. bernard.testa@ict.unil.ch
Mayer
J
J
D001711:Biotransformation; D002626:Chemistry, Pharmaceutical; D013379:Substrate Specificity; D015262:Xenobiotics / Q000378:metabolism*
D015262:Xenobiotics