Drug Bioactivation Covalent Binding to Target Proteins and Toxicity Relevance

Abstract

A number of therapeutic drugs with different structures and mechanisms of action have been reported to undergo metabolic activation by Phase I or Phase II drug-metabolizing enzymes. The bioactivation gives rise to reactive metabolites/intermediates, which readily confer covalent binding to various target proteins by nucleophilic substitution and/or Schiff's base mechanism. These drugs include analgesics (e.g., acetaminophen), antibacterial agents (e.g., sulfonamides and macrolide antibiotics), anticancer drugs (e.g., irinotecan), antiepileptic drugs (e.g., carbamazepine), anti-HIV agents (e.g., ritonavir), antipsychotics (e.g., clozapine), cardiovascular drugs (e.g., procainamide and hydralazine), immunosupressants (e.g., cyclosporine A), inhalational anesthetics (e.g., halothane), nonsteroidal anti-inflammatory drugs (NSAIDSs) (e.g., diclofenac), and steroids and their receptor modulators (e.g., estrogens and tamoxifen). Some herbal and dietary constituents are also bioactivated to reactive metabolites capable of binding covalently and inactivating cytochrome P450s (CYPs). A number of important target proteins of drugs have been identified by mass spectrometric techniques and proteomic approaches. The covalent binding and formation of drug-protein adducts are generally considered to be related to drug toxicity, and selective protein covalent binding by drug metabolites may lead to selective organ toxicity. However, the mechanisms involved in the protein adduct-induced toxicity are largely undefined, although it has been suggested that drug-protein adducts may cause toxicity either through impairing physiological functions of the modified proteins or through immune-mediated mechanisms. In addition, mechanism-based inhibition of CYPs may result in toxic drug-drug interactions. The clinical consequences of drug bioactivation and covalent binding to proteins are unpredictable, depending on many factors that are associated with the administered drugs and patients. Further studies using proteomic and genomic approaches with high throughput capacity are needed to identify the protein targets of reactive drug metabolites, and to elucidate the structure-activity relationships of drug's covalent binding to proteins and their clinical outcomes.

Metabolic Disposition of Osimertinib in Rats, Dogs, and Humans: Insights into a Drug Designed to Bind Covalently to a Cysteine Residue of Epidermal Growth Factor Receptor

“…Taken together, these findings strongly suggest that the difference in AUC between radioactivity and osimertinib, AZ5104, and AZ7550 is due to osimertinib-related material bound to plasma proteins, especially albumin. No findings in the clinical or preclinical studies to date indicate that covalent binding of osimertinib and/or its metabolites to proteins is associated with any toxicologic sequelae, such as idiosyncratic liver or immune-mediated toxicity (Zhou et al, 2005;Park et al, 2005). In humans, the most abundant circulating metabolites observed in steady-state plasma extracts from patients dosed with non-radiolabeled osimertinib at 80 mg were AZ5104 (N-demethylation on the indole) and AZ7550 (N-demethylation on the dimethyl amine), representing 8% and 6% of total drug-related material, respectively.…”

Identification of 20(S)-Protopanaxadiol Metabolites in Human Liver Microsomes and Human Hepatocytes

“…The covalent binding and formation of drug-protein adducts are generally considered to be related to drug toxicity (Zhou et al, 2005). To evaluate their reactivity, nucleophilic GSH (5 mM) was incorporated as an exogenous agent to trap 24,25-epoxide metabolites of PPD in incubations of NADPH-supplemented human liver microsomes.…”

Liquid Chromatography/Tandem Mass Spectrometry Detection of Covalent Binding of Acetaminophen to Human Serum Albumin

“…Drugs can be bioactivated both by phase I and phase II enzymes to reactive electrophilic intermediates, which subsequently react with nucleophilic sites in macromolecules to form covalent adducts to proteins (Evans et al, 2004;Zhou et al, 2005). Covalent binding to proteins with subsequent inactivation of enzymes and/or disruption of cellular signaling processes are events that are thought to be related to the onset of ADRs (Zhou et al, 2005). By serving as haptens, drug-protein adducts may also trigger the autoimmune reactions, which are often observed in case of idiosyncratic drug reactions (IDRs) (Uetrecht, 1999;Park et al, 2000).…”