Drug bioactivation, covalent binding to target proteins and toxicity relevance

Zhou, Shufeng, Chan, Eli, Duan, Wei, Huang, Min and Chen, Yu-Zong 2005, Drug bioactivation, covalent binding to target proteins and toxicity relevance, Drug metabolism reviews, vol. 37, no. 1, pp. 41-213.

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Title Drug bioactivation, covalent binding to target proteins and toxicity relevance
Author(s) Zhou, Shufeng
Chan, Eli
Duan, Wei
Huang, Min
Chen, Yu-Zong
Journal name Drug metabolism reviews
Volume number 37
Issue number 1
Start page 41
End page 213
Publisher Informa Healthcare
Place of publication New York, N.Y.
Publication date 2005-01
ISSN 0360-2532
1097-9883
Keyword(s) metabolic intermediate
bioactivation
covalent binding
cytochrome P450
toxicity
Summary 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 targetsof reactive drug metabolites, and to elucidate the structure-activity relationships of drug's covalent binding to proteins and their clinical outcomes.
Language eng
Field of Research 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2005, Taylor & Francis Inc.
Persistent URL http://hdl.handle.net/10536/DRO/DU:30009251

Document type: Journal Article
Collection: School of Medicine
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