Bioactivation and reactivity research advances - 2021 year in review

Abstract

This year's review on bioactivation and reactivity began as a part of the annual review on biotransformation and bioactivation led by Cyrus Khojasteh (see references). Increased contributions from experts in the field led to the development of a stand alone edition for the first time this year focused specifically on bioactivation and reactivity. Our objective for this review is to highlight and share articles which we deem influential and significant regarding the development of covalent inhibitors, mechanisms of reactive metabolite formation, enzyme inactivation, and drug safety. Based on the selected articles, we created two sections: (1) reactivity and enzyme inactivation, and (2) bioactivation mechanisms and safety (Table 1). Several biotransformation experts have contributed to this effort from academic and industry settings.[Table: see text].

Figure 1.

(A) AO substrates demonstrating different degrees of inactivation of the wild-type and L438V enzymes, presumably due to different substrate turnover rates resulting in different rates of ROS production. Arrows indicate site of AO oxidation. (B) AO mechanism of substrate oxidation and catalytic cycle. The authors propose that ROS produced as a consequence of substrate oxidation inactivates the enzyme via desulfuration of the molybedenum cofactor.

Figure 2.

Biomimetic chemical synthesis of ICT-BBA adduct and proposed bioactivation pathway for the formation of ICT-BBA adduct. BBA: 4-bromobenzylamine; m-CPBA: m-chloroperbenzoic acid.

Figure 3.

Proposed metabolism of evobrutinib to its major metabolites in healthy volunteers.

Figure 4.

Proposed bioactivation pathway of atomoxetine.

Figure 5.

The proposed bioactivation pathway of aromatic amines (A) Structure activity relationship of mutagenic compounds versus using the removal of H-bond donors, introduction of steric repulsion groups, decreasing the stability of the ArNH⁻ formation, introduction of electrostatic repulsion groups and disruption of π–π interaction with DNA bases (B).

Figure 6.

(a) Overall reported trimethoprim (TMP) and its reactive metabolites. In vivo rat studies, TMP formed significant hepatic covalent binding but not with α-hydroxy-TMP (TMP-OH) and α-keto-TMP (TMP = O). In vitro TMP-OH and TMP-S formed covalent binding in S9 fractions with liver ⪢ skin. Finally, no human SULT was found to convert TMP-OH to TMP-S. In the two lower boxes strucutres of TMP reactive metabolites and primary metabolites reported by Goldman et al. 2016 and Nolte et al. 2020. (b) (A) The reaction for the nevirapine (NVP) CYP-mediated metabolism to 12-hydroxy NVP (12-OH-NVP) and its subsequent metabolism by human sulfotransferases (SULT). (B) Minoxidil formation of pharmacologically active minoxidil sulfate.

Figure 7.

Proposed mechanism for clozapine bioactivation in cardiomyocytes leading to protein adduction and mitochondrial dysfunction as precursors to cell death or a toxic immune response resulting in cardiotoxicity.

Figure 8.

Metabolic pathway for the diphenyl NSAID diclofenac that undergoes bioactivation to form quinone-species metabolites.

Figure 9.

Bioactivation pathways of labetalol.

Figure 10.

Bioactivation pathways of duocarmycin ICT2700.

Figure 11.

Structure of FXla-6f along with putative bioactivation pathways of oxidative ipso-substituted metabolite M2 and aniline metabolite M6.

Figure 12.

The five propionic acid NSAIDs investigated in the work by Hashizum et al. (A) and the steps of propionic acid NSAID acyl-CoA conjugation by ASCL1 (B).

Figure 13.

Proposed bioactivation pathway of tandutinib. Figure adapted from Al-Shakliah et al. (2021). KCN: potassium cyanide. Predicted structures of four cyano adducts (TNDCN588, TNDCN546, TNDCN574, and TNDCN602) are shown.

Figure 14.

Proposed mechanism of idiosyncratic drug-induced liver injury (IDILI).