Designing Safer (Soft) Drugs by Avoiding the Formation of Toxic and Oxidative Metabolites

Living organisms possess not only fine-tuned metabolic mechanisms for endogenous chemicals but also several defensive mechanisms to detoxify xenobiotics. Most metabolic processes that eliminate invading foreign chemicals by transforming them into more hydrophilic or more easily conjugated compounds are oxidative in nature. Unfortunately, many of these mechanisms are indiscriminate, and detoxifying enzymes, such as cytochrome P450 or N-acetyltransferase, can generate toxic reactive intermediates such as epoxides or radicals from otherwise nontoxic compounds (1 ,2 ). Chemicals and xenobiotics, therefore, are not always metabolized only into more hydrophilic and less toxic substances, but also into highly reactive chemical species, which then can react with various macromolecules and cause tissue damage or elicit antigen production.