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The Renewal of Interest in Nitroaromatic Drugs
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Nicolas Primas, Caroline Ducros, Patrice Vanelle, Pierre Verhaeghe
Fexinidazole (11), like other nitrodrugs, is a prodrug that requires activation by a nitroreductase (Wyllie et al. 2016a). A first L. donovani type 1 NTR (Ld)NTR1 was discovered and was found essential for parasite growth and replication, as it cannot be experimentally repressed (Voak et al. 2013). However, it was proved possible to generate a parasite strain overexpressing this (Ld)NTR1 in which a 15-fold increase in sensitivity to fexinidazole (11) was observed (Wyllie et al. 2012), confirming the direct involvement of (Ld)NTR1 in the activation of fexinidazole (Wyllie et al. 2013).
Metronidazole
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Anaerobic bacteria may also develop resistance to metronidazole by removing elements in the series of electron transport molecules. Pyruvate oxidoreductase (POR) and ferredoxin are particularly affected by appropriate compensatory modifications of the normal fermentative pathways (Edwards, 1993a). This decrease in nitroreductase activity is associated with decreased uptake of the drug, because entry of the drug into the target cell depends on the rate of reduction of the nitro group.
General toxicology
Published in Timbrell John, Study Toxicology Through Questions, 2017
(a) Nitroreductase; (b) N-acetyltransferase; (c) cytochrome P450; (d) glutathione-Stransferase; (e) epoxide hydrolase; (f) chemical rearrangement; (g) glucuronysyltransferase or sulphotransferase; (h) γ-glutamyltransferase; (i) glycinase; (j) acetyltransferase.
Nanomicelles for GLUT1-targeting hepatocellular carcinoma therapy based on NADPH depletion
Published in Drug Delivery, 2023
Congyi Zhang, Zehui Liu, Feng Wang, Bin Zhang, Xirui Zhang, Peiwen Guo, Tianwei Li, Sheng Tai, Changmei Zhang
There are several important redox material pairs in cells, among which NADP+/NADPH and oxidized/reduced glutathione (GSSG/GSH) are more closely involved in the redox process of the body. GSH will be oxidized to GSSG, and GSSG can also be reduced to GSH with nicotinamide adenine dinucleotide phosphate (NADPH) participation, which makes the GSH/GSSG redox be in a relatively constant equilibrium state. It will lead to redox imbalance when the GSH generation is insufficient, too much NADPH is consumed, or GSSG cannot be reduced in time (Smith et al., 1996). It is believed that the action of NADPH involves the generation and contribution of GSH as the cofactor. NADPH will participate in the process of GSSG to reductive GSH (Deponte, 2013; Gorai et al., 2022). Logically, NADPH depletion will lead to decrease of GSH. Therefore, researchers design a kind of self-assemble micelles, in which the hydrophobic core is nitroimidazole. The nitroimidazole moiety is reduced by the over-expressed nitroreductase with reduced NADPH as the cofactor, resulting in transient deletion of NADPH and GSH (Guo et al., 2020). Finally, the imbalance of redox in tumor cells results in tumor cell death.
L. reuteri JMR-01 adjuvant 12C6+ irradiation exerts anti-colon carcinoma effects by modulating the gut microbiota in mice
Published in International Journal of Radiation Biology, 2023
Jin Bai, Shuyang Wang, Fuqiang Xu, Miaoyin Dong, Junkai Wang, Xisi Sun, Guoqing Xiao
As shown in Figure 7, fecal enzyme activities in each group especially tumor control group were increased compared with normal control group, suggesting fecal enzymes were closely related to the occurrence of colon carcinoma. The results indicated that IR, IR + LP, IR + IP and IR + LP + IP treatments reduced the activities of fecal enzymes compared with tumor control group. In particular, IR + LP + IP group showed a marked decreasing nitroreductase activities in comparison with other experiment groups. At 0–16 d, IR + LP + IP group showed a slow growth rate compared with tumor control group and other treatment groups. During 16–30 d, fecal enzyme activities were increasing with the tumor rapid growth except for IR + LP, which may be owing to the death of half the mice in LP group. During 30–50 d, the survival rates of tumor mice were decreasing due to the death of mice with larger tumor volumes, which may lead to decreased fecal enzyme activities. The results indicated that JMR-01 adjuvant 12C6+ irradiation could decrease fecal enzyme activities.
Role of Heme Iron in the Association Between Red Meat Consumption and Colorectal Cancer
Published in Nutrition and Cancer, 2018
Arianna Sasso, Giovanni Latella
The gut microbiota is able to modulate the activity of the enzyme nitroreductase. Probiotic bacteria such as Lactobacillus casei and L. acidophilus (72–74) reduce nitroreductase activity and the risk of CRC. Conversely, diets rich in meat and low in fiber increase the nitroreductase activity of intestinal bacteria (75). Since nitrosation is modulated by the intestinal bacterial flora, it may be speculated that the increased nitrosation induced by heme occurs through a modification of the gut microbiota induced by heme itself, as hypothesized for mucolysis. In rats, a heme-based diet has been reported to reduce the levels of Lactobacilli (74,76), which can inhibit nitroreductase activity. However, further work is required to elucidate these mechanisms.