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Biochemical Methods of Studying Hepatotoxicity
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Prasada Rao S. Kodavanti, Harihara M. Mehendale
NADPH-cytochrome P450 reductase is conveniently measured by its NADPH-cytochrome c reductase activity (Phillips and Langdon, 1962). The assay is an indirect measure of NADPH cytochrome P450 reductase activity; measurement of actual NADPH cytochrome P450 reductase activity requires anaerobic conditions and rapid reaction techniques (Peterson et al., 1978). A small peptide of the reductase is required for NADPH cytochrome P450 reductase activity but not cytochrome c reductase activity; if no proteolysis has occurred, the two activities are closely correlated (Vermilion and Coon, 1978).
Intraperitoneal chemotherapy
Published in Tom Cecil, John Bunni, Akash Mehta, A Practical Guide to Peritoneal Malignancy, 2019
Mitomycin C was the drug used in the first and, to date, only prospective randomised controlled trial regarding CRS and HIPEC in patients with CPM and was the first drug ever used in a human HIPEC procedure [16, 17]. Cytotoxicity of mitomycin C is achieved by formation of DNA crosslinks [43]. However, native mitomycin C has virtually no cytotoxic effect, but requires a process of bioreductive activation to enable DNA crosslinking. This activation is mediated by various enzymes, including cytochrome P450 reductase [43–45]. Therefore, the antitumour potency of mitomycin C is strongly influenced by enzymes expressed in the tumour tissue. Several studies have shown an association between expression levels of various bioreducing enzymes in tumours and tumour cell lines and sensitivity to mitomycin C-based cytotoxicity [46–48]. In addition, genetic variation in genes encoding various bioreducing enzymes has been shown to be associated with outcomes of mitomycin C-based CRS and HIPEC for CPM [49]. Intraperitoneal use of mitomycin C has been associated with sometimes severe neutropenia. Some studies have also reported relatively high rates of enteric fistulae following CRS and HIPEC with mitomycin C [50–53].
Metabolism of Chemical Carcinogens by Intestinal Tissue
Published in Herman Autrup, Gary M. Williams, Experimental Colon Carcinogenesis, 2019
The columnar cells of the epithelium originate in the crypts and migrate toward the intestinal lumen as they mature and undergo differentiation. During this process a variety of enzymes including some of the drug metabolizing enzymes such as microsomal cytochrome P-450 and NADPH-cytochrome P-450 reductase31 are synthesized. The level of cytochrome P-450 and the activity of BP-monooxygenase are approximately ten-fold higher in the fully differentiated epithelial cells as compared to the crypt cells of the small intestine.31
Metabolism of the antipsychotic drug olanzapine by CYP3A43
Published in Xenobiotica, 2022
Jie Zhao, David Machalz, Sijie Liu, Clemens Alexander Wolf, Gerhard Wolber, Maria Kristina Parr, Matthias Bureik
The fission yeast strains that coexpress human cytochrome P450 reductase (CPR) and either CYP1A2, CYP2D6, CYP3A4, CYP3A5, CYP3A7, or CYP3A43.1, respectively, have been described previously (Drăgan et al. 2011; Neunzig et al. 2011; 2012; Durairaj et al. 2019), while the three strains expressing the CYP3A43 mutants were cloned in this investigation. All strains used in this study are listed in Table 1. The sites of olanzapine metabolism were predicted by SMARTCyp (Rydberg et al. 2010), a web-based software that predicts CYP-mediated metabolic liability of heavy substrate atoms (Supplementary Table 2). Metabolites M1 (2′-hydroxymethyl olanzapine) and M2 (N-desmethyl olanzapine) showed the highest probability of matching with a predicted SoO, followed by M3 (olanzapine nitrenium ion), M4 (3′-hydroxymethyl olanzapine) and M5 (2-hydroxymethyl olanzapine). Three of these olanzapine metabolites (M2, M3 and M5) have been reported before (Soderberg and Dahl 2013; Geib et al. 2020). Thus, all of these metabolites were included in our analysis. Moreover, we also looked for M6 (2-formyl olanzapine) and M7 (2-carboxy olanzapine) as they result from further biotransformation of M5 and, moreover, M7 is well known (Soderberg and Dahl 2013). The chemical structures of all metabolites are shown in Figure 1.
Hypoxia-activated prodrug derivatives of anti-cancer drugs: a patent review 2006 – 2021
Published in Expert Opinion on Therapeutic Patents, 2022
Emilie Anduran, Ludwig J Dubois, Philippe Lambin, Jean-Yves Winum
Davis et al. from Angiogene Pharm Ltd and Gray Lab Cancer Res Trust described a wealth of novel HAP of nucleoside analogs having cytotoxic activity such as cytarabine, fludarabine, capecitabine, or vidarabine [41]. Fourteen compounds are exemplified in this patent application with a nitroaromatic HAP trigger (nitroimidazole, nitrothiophene, or nitrofurane) connected to the purine or pyrimidine nucleobase via a carbamate bond (see some examples compounds 8–11 in Figure 3). Compounds are claimed to efficiently release cytotoxic nucleoside analogs: (i) under anoxic condition in liver homogenates or upon the action of cytochrome P450 reductase and (ii) upon radiolysis or pulse radiolysis. No data are available on antitumoral effect in vitro and in vivo, limiting the scope of this patent.
Kinetics of dextromethorphan-O-demethylase activity and distribution of CYP2D in four commonly-used subcellular fractions of rat brain
Published in Xenobiotica, 2019
Barent N. DuBois, Farideh Amirrad, Reza Mehvar
In addition to the possibility of the presence of a different CYP2D isoform in the mitochondria, other factors may have also contributed to the apparent lower affinity of mitochondrial CYP2D observed in our study. For instance, post-translational modification of CYP2D for targeting to the mitochondria (Anandatheerthavarada et al., 1999; Boopathi et al., 2000; Dasari et al., 2006) may affect its affinity. Another contributing factor to the lower affinity in the mitochondria might be related to the major differences between the mitochondria and microsomes in their CYP450 electron transferring mechanisms. In the microsomes, cytochrome P450 reductase (CPR) is responsible for the electron transfer to CYP450, and both CYP450 and CPR are integrally membrane-bound proteins. However, the electron transfer system in mitochondria consists of two soluble proteins, adrenodoxin (Adx) and adrenodoxin reductase (Adr), which are present in the inner membrane matrix. During the preparation of mitochondrial fractions, it is possible that the inner and/or outer membranes of some mitochondria are disrupted, resulting in a reduction in the concentrations of Adx and Adr proteins in the mitochondrial matrix (Dasari et al., 2006; Sangar et al., 2009). Consequently, the apparently low affinity (Figure 2(B)) and intrinsic clearance (Figure 2(C)) of the CYP2D-mediated DOD in mitochondria, compared with the respective values in the microsomes, could be partially related to some loss of Adx and Adr during the preparation of mitochondria.