Going Beyond Common Drug Metabolizing Enzymes: Case Studies of Biotransformation Involving Aldehyde Oxidase, γ-Glutamyl Transpeptidase, Cathepsin B, Flavin-Containing Monooxygenase, and ADP-Ribosyltransferase
| Autor: | Driscoll Jp, Donglu Zhang, Jason Halladay, Fan Pw, Khojasteh Sc |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pharmaceutical Science Flavin-containing monooxygenase Pharmacology Cathepsin B Substrate Specificity Xenobiotics 03 medical and health sciences 0302 clinical medicine Species Specificity Animals Humans Gamma-glutamyltransferase Aldehyde oxidase Biotransformation chemistry.chemical_classification ADP Ribose Transferases biology Chemistry Drug discovery Cytochrome P450 gamma-Glutamyltransferase Monooxygenase Aldehyde Oxidase 030104 developmental biology Enzyme Biochemistry 030220 oncology & carcinogenesis biology.protein Oxygenases |
| Zdroj: | Drug metabolism and disposition: the biological fate of chemicals. 44(8) |
| ISSN: | 1521-009X |
| Popis: | The significant roles that cytochrome P450 (P450) and UDP-glucuronosyl transferase (UGT) enzymes play in drug discovery cannot be ignored, and these enzyme systems are commonly examined during drug optimization using liver microsomes or hepatocytes. At the same time, other drug-metabolizing enzymes have a role in the metabolism of drugs and can lead to challenges in drug optimization that could be mitigated if the contributions of these enzymes were better understood. We present examples (mostly from Genentech) of five different non-P450 and non-UGT enzymes that contribute to the metabolic clearance or bioactivation of drugs and drug candidates. Aldehyde oxidase mediates a unique amide hydrolysis of GDC-0834 (N-[3-[6-[4-[(2R)-1,4-dimethyl-3-oxopiperazin-2-yl]anilino]-4-methyl-5-oxopyrazin-2-yl]-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide), leading to high clearance of the drug. Likewise, the rodent-specific ribose conjugation by ADP-ribosyltransferase leads to high clearance of an interleukin-2-inducible T-cell kinase inhibitor. Metabolic reactions by flavin-containing monooxygenases (FMO) are easily mistaken for P450-mediated metabolism such as oxidative defluorination of 4-fluoro-N-methylaniline by FMO. Gamma-glutamyl transpeptidase is involved in the initial hydrolysis of glutathione metabolites, leading to formation of proximate toxins and nephrotoxicity, as is observed with cisplatin in the clinic, or renal toxicity, as is observed with efavirenz in rodents. Finally, cathepsin B is a lysosomal enzyme that is highly expressed in human tumors and has been targeted to release potent cytotoxins, as in the case of brentuximab vedotin. These examples of non-P450- and non-UGT-mediated metabolism show that a more complete understanding of drug metabolizing enzymes allows for better insight into the fate of drugs and improved design strategies of molecules in drug discovery. |
| Databáze: | OpenAIRE |
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