Biotransformation and bioactivation reactions – 2015 literature highlights

Figures & data

Table

	Title	Authors	Source
1	Biotransformation of Benzbromarone: Elucidation of a P450 Catalyzed Novel Bioactivation Pathway	Yumina Kitagawara, Tomoyuki Ohe, Kumiko Tachibana, Kyoko Takahashi, Shigeo Nakamura, and Tadahiko Mashino	Drug Metabolism Disposition 43:1303–1306, 2015
2	Lipid Peroxide–Mediated Oxidative Rearrangement of the Pyrazinone Carboxamide Core of Neutrophil Elastase Inhibitor AZD9819 in Blood Plasma Samples	Chungang Gu, Richard J. Lewis, Andrew S. Wells, Per H. Svensson, Vinayak P. Hosagrahara, Eskil Johnsson, and Gösta Hallström	Drug Metabolism Disposition 43:1441–1449, 2015
3	The Oxidative Ring Opening of MRX-I by Non-P450 Enzymes	Jian Meng, Dafang Zhong, Liang Li, Zhengyu Yuan, Hong Yuan, Cen Xie, Jialan Zhou, Chen Li, Mikhail Fedorovich Gordeev, Jinqian Liu, and Xiaoyan Chen	Drug Metabolism Disposition 43:646–659, 2015
4	Formation of Sulfur Adducts of N-Acetyl-p-benzoquinoneimine, an Electrophilic Metabolite of Acetaminophen In Vivo: Participation of Reactive Persulfides	Yumi Abiko, Isao Ishii, Shotaro Kamata, Yukihiro Tsuchiya, Yasuo Watanabe, Hideshi Ihara, Takaaki Akaike, and Yoshito Kumagai	Chemical Research in Toxicology 28:1796–1802, 2015
5	The c-Met Tyrosine kinase inhibitor JNJ-38877605 Causes Renal Toxicity through Species-Specific Insoluble Metabolite Formation	Martijn P. Lolkema, Hilde H. Bohets, Hendrik-Tobias Arkenau, Ann Lampo, Erio Barale, Maja J. A. DeJonge, Leni van Doorn, Peter Hellemans, Johann S. de Bono, and Ferry A. L. M. Eskens	Clinical Cancer Research 21:2297–2304, 2015
6	The Metabolism of 4-Bromoaniline in the Bile-cannulated Rat: Application of ICPMS (^79/81Br), HPLC-ICPMS, and HPLC-oaTOFMS	Catherine Duckett, Michael McCullagh, and Ian D Wilson	Xenobiotica 45:672–680, 2015
7	Stereospecific Metabolism of the Tobacco-specific Nitrosamine, NNAL	Shannon Kozlovich, Gang Chen, Philip Lazarus	Chemical Research in Toxicology 28:2112–2119, 2015
8	Molecular Mechanism of Metal-independent Decomposition of Organic Hydroperoxides by Halogenated Quinoid Carcinogens and the Potential Biological Implications	Chun-Hua Huang, Fu-Rong Ren, Guo-Qiang Shan, Hao Qin, Li Moao and Ben-Zhan Zhu	Chemical Research in Toxicology 28:831–837, 2015
9	Hepatic Metabolism of Carcinogenic β-Asarone	Alexander T. Cartus, Simone Stegmüller, Nadine Simson, Andrea Wahl, Slyvia Neef, Harald Kelm and Dieter Schrenk	Chemical Research in Toxicology 28:1760–1773, 2015
10	Pharmacokinetics and Metabolism of Delamanid, a Novel Anti-Tuberculosis Drug, in Animals and Humans: Importance of Albumin Metabolism In Vivo	Katsunori Sasahara, Yoshihiko Shimokawa, Yukihiro Hirao, Noriyuki Koyama, Kazuyoshi Kitano, Masakazu Shibata, and Ken Umehara	Drug Metabolism Disposition 43:1267–1276, 2015
11	Metabolic Mechanism of Delamanid, a New Anti-Tuberculosis Drug, in Human Plasma	Yoshihiko Shimokawa, Katsunori Sasahara, Noriyuki Koyama, Kazuyoshi Kitano, Masakazu Shibata, Noriaki Yoda, and Ken Umehara	Drug Metabolism Disposition 43:1277–1283, 2015
12	Elucidating the Mechanisms of Formation for Two Unusual Cytochrome P450-Mediated Fused Ring Metabolites of GDC-0623, a MAPK/ERK Kinase Inhibitor	Ryan H. Takahashi, Shuguang Ma, S. J. Robinson, Qin Yue, Edna F. Choo, S. Cyrus Khojasteh	Drug Metabolism Disposition 43:1929–1933, 2015
13	A Novel Reaction Mediated by Human Aldehyde Oxidase: Amide Hydrolysis of GDC-0834	Jasleen K. Sodhi, Susan Wong, Donald S. Kirkpatrick, Lichuan Liu, S. Cyrus Khojasteh, Cornelis E. C. A. Hop, John T. Barr, Jeffrey P. Jones, and Jason S. Halladay	Drug Metabolism and Disposition 43:908–915, 2015

Figure 1. Metabolic Scheme of benzbromarone in rat and human liver microsomal systems (Kitagawara et al., 2015). Metabolites M4, M5 and M6 were previously reported (McDonald & Rettie, 2007; Kobayashi et al., 2012).

Figure 2. Proposed mechanisms for formation of metabolite M1 (A) and M2 (B).

Figure 3. Alternate mechanism for formation of M2.

Figure 4. Chemical structures of AZD9819 (1) and its rearranged product 2 (Gu et al., 2015).

Figure 5. Step 1: Mechanism of oxidation of 1 to the epoxide (3). Step 2: Rearrangement of epoxide (3) to the corresponding oxazole 2 (Gu et al., 2015).

Figure 6. Proposed metabolic scheme of 1 in humans (Meng et al., 2015) and chemical structure of linezolid (2).

Figure 7. Mechanism of formation of metabolites 3 and 4 by FMO-catalyzed metabolism of 1 (Meng et al., 2015).

Figure 8. (A) Formation of metabolite 5 (Meng et al., 2015). (B) Alternative mechanism for the formation of 5 from intermediate 15.

Figure 9. Conjugation of NAPQI with GSSH and CysSSSH.

Figure 10. Metabolism of quinoline-containing c-Met inhibitors by AO to lactam derivatives.

Figure 11. Structures of 4-bromoaniline and its major metabolites in rats.

Figure 12. Regio- and stereoslective glucuronidation of NNAL and (R)-NNAL-O-Gluc/(S)-NNAL-O-Gluc ratio in incubations with human liver microsomes stratified by UGT2B17 genotype. *1 refers to the wild-type UGT2B17 allele; *2 refers to the UGT2B17 gene deletion allele. ‡, p = 0.012.

Figure 13. Proposed mechanism for ^•OH production by tetrachloro-1,4-benzoquinone (TCBQ) and organic hydroperoxides (ROOH), forming a trichlorohydroperoxyl-1,4-benzoquinone (TrCBQ-OOH) intermediate, which can decompose homolytically to produce the •OH and the trichloro-hydroxy-1,4-benzoquinone radical (TrCBQ-O^•).

Figure 14. Hepatic metabolism of β-asarone. Formation of the epoxide is suggested to represent the bioactivation pathway to a (geno)toxic metabolite.

Figure 15. (A) Catalytic conversion of delamanid to M1 by albumin, (B) proposed mechanism of this reaction proceeding via a nucleophile (Nu) from albumin, and (C) the chemical structure of pretomanid.

Figure 16. Proposed reaction mechanisms for the formation of M14 and M13 from GDC-0623.

Figure 17. The structure of MEK inhibitors that include hydroxamate side chains, similarly to GDC-0623.

Figure 18. Aldehyde oxidase hydrolysis of GDC-0834 to M1 and M2.

Figure 19. Proposed reaction mechanism for hydrolysis of GDC-0834 by aldehyde oxidase (AO).

Kitagawara Y, Ohe T, Tachibana K, et al. (2015). Novel bioactivation pathway of benzbromarone mediated by cytochrome P450. Drug Metab Dispos 43:1303–1306.

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McDonald MG, Rettie AE. (2007). Sequential metabolism and bioactivation of the hepatotoxin benzbromarone: formation of glutathione adducts from a catechol intermediate. Chem Res Toxicol 20:1833–1842.

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Kobayashi K, Kajiwara E, Ishikawa M, et al. (2012). Identification ofisozymes involved in benzbromarone metabolism in human liver microsomes. Biopharm Drug Dispos 33:466–473.

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Gu C, Lewis RJ, Wells AS, et al. (2015). Lipid peroxide-mediated oxidative rearrangement of the pyrazinone carboxamide core of neutrophil elastase inhibitor AZD9819 in blood plasma samples. Drug Metab Dispos 43:1441–1449.

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Meng J, Zhong D, Li L, et al. (2015). Metabolism of MRX-I, a novel antibacterial oxazolidinone, in humans: The oxidative ring opening of 2,3-dihydropyridin-4-one catalyzed by non-P450 enzymes. Drug Metab Dispos 43:646–659.

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