Mechanism of reduction of nitrofurantoin on liver microsomes

Leskovac, Vladimir; Popović, M.

doi:10.1016/s0031-6989(80)80058-0

Cited by 13 publications

(4 citation statements)

References 9 publications

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“…The mechanisms of sepin-1 reduction (M1 and M2) and dimer formation (M3–M5) are not clear yet. The liver microsomes involved in the formation of reduced metabolite is known ( Leskovac and Popovic, 1980 ; Placidi et al, 1993 ; Wang et al, 2005 ). Our study suggested that multiple P450s enzymes contribute to sepin-1 metabolism.…”

Section: Discussionmentioning

confidence: 99%

The Metabolism of Separase Inhibitor Sepin-1 in Human, Mouse, and Rat Liver Microsomes

Zhang

Gorantla

et al. 2018

Front. Pharmacol.

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Separase, a known oncogene, is widely overexpressed in numerous human tumors of breast, bone, brain, blood, and prostate. Separase is an emerging target for cancer therapy, and separase enzymatic inhibitors such as sepin-1 are currently being developed to treat separase-overexpressed tumors. Drug metabolism plays a critical role in the efficacy and safety of drug development, as well as possible drug–drug interactions. In this study, we investigated the in vitro metabolism of sepin-1 in human, mouse, and rat liver microsomes (RLM) using metabolomic approaches. In human liver microsomes (HLM), we identified seven metabolites including one cysteine–sepin-1 adduct and one glutathione–sepin-1 adduct. All the sepin-1 metabolites in HLM were also found in both mouse and RLM. Using recombinant CYP450 isoenzymes, we demonstrated that multiple enzymes contributed to the metabolism of sepin-1, including CYP2D6 and CYP3A4 as the major metabolizing enzymes. Inhibitory effects of sepin-1 on seven major CYP450s were also evaluated using the corresponding substrates recommended by the US Food and Drug Administration. Our studies indicated that sepin-1 moderately inhibits CYP1A2, CYP2C19, and CYP3A4 with IC50 < 10 μM but weakly inhibits CYP2B6, CYP2C8/9, and CYP2D6 with IC50 > 10 μM. This information can be used to optimize the structures of sepin-1 for more suitable pharmacological properties and to predict the possible sepin-1 interactions with other chemotherapeutic drugs.

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Section: Discussionmentioning

confidence: 99%

The Metabolism of Separase Inhibitor Sepin-1 in Human, Mouse, and Rat Liver Microsomes

Zhang

Gorantla

et al. 2018

Front. Pharmacol.

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“…Peterson et al, 1982a), guinea pigs (age and sex not specified, 400-600 g, Leskovac and Popovic, 1980), or Erhlich ascites tumor cells (Biaglow et al, 1977). This results in a transient nitroaromatic anion radical that may react with molecular oxygen, producing superoxide anion free radical, and possibly hydrogen peroxide and the regeneration of nitrofurantoin.…”

Section: G Sasame Andmentioning

confidence: 99%

“…Jonen and Kaufman (1980) reported that in rats (male, Sprague Dawley, 250-300 g, age not specified), 3-methylcholanthrene and P-nitrofiavone, but not phenobarbital, pretreatment in creased the clearance of napthofurantoin from the isolated perfused liver and increased the formation of a polar metabolite, similar to a hydroxylated furan derivative ( l-[[(5-ac(-nitro-4,5dihydro-4-oxo-2-furanyl)-methylene]amino|-2,4imidazolidinedione) (Olivard et al, 1976) Reductive metabolism of nitrofurantoin under anaerobic conditions has been described in both rodents and bacteria. Without oxygen, nitrofurantoin is believed to be permanently reduced to nitroso and/or hydroxy lamine forms (Mason and Holtzman, 1975b, Biaglow et al , 1977; Leskovac and Popovic, 1980). Aufrere et al ( 1978) studied the reductive metabolism of nitrofurantoin under anaerobic conditions with young male Sprague Dawley rats (60 g) and reported that the metabolism of nitrofurantoin was greatest in homogenates of cecum and colon contents of germ-free acclimatized and control rats but not germ-free rats and in liver, small intestine walls, and kidney (in decreasing order of activity) in all groups.…”

Section: G Sasame Andmentioning

confidence: 99%

NTP technical report on the toxicology and carcinogenesis studies of nitrofurantoin (CAS no. 67-20-9) in F344/N rats and B6C3F mice (feed studies) / National Toxicology Program.

1989

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Nitrofurantoin was studied and evaluated because of its widespread use as a drug for treating urinary tract infections in humans, its structural relationship to known carcinogenic 5-nitrofuran compounds, and the lack of adequate studies to assess its carcinogenicity Toxicology and carcinogenesis studies of nitrofurantoin were conducted by administering nitrofurantoin (greater than 99% pure) in feed to groups of F344/N rats and B6C3Fi mice of each sex for 14 days, 13 weeks, or 2 years. Fourteen-Day and Thirteen-Week Studies: None of the rats (at dietary concentrations up to 20,000 ppm) died before the end of the 14-day studies. Rats that received 5,000, 10,000, or 20,000 ppm lost weight. Four of five male and 4/5 female mice that received 10,000 ppm and 1/5 females that received 5,000 ppm nitrofurantoin died before the end of the studies. Mice that received 5,000 ppm and male mice that received 10,000 ppm lost weight. In the 13-week studies, final mean body weights of rats that received 2,500, 5,000, or 10,000 ppm were 10%, 34%, or 47% lower than that of the controls for males and 15%, 31%, or 41% lower for females. Feed consumption by dosed and control rats was generally similar. Degeneration of the germinal epithelium of the seminiferous tubules of the testis was observed in male rats that received 2,500 to 10,000 ppm nitrofurantoin. Necrosis of the ovarian follicles was observed in 8/10 female rats that received 10,000 ppm, in 3/10 females that received 5,000 ppm, and in 1/10 that received 2,500 ppm. For mice, final mean body weights of the 5,000-ppm groups were 13% lower than that of the controls for males and 15% lower for females. Two of 10 male mice that received 5,000 ppm and 1/10 males that received 300 ppm died before the end of the 13-week studies. Estimated feed consumption was similar for dosed and control groups. Degeneration of the germinal epithelium of the testis was observed in males that received 1,300 to 5,000 ppm; necrosis of the ovarian follicles was observed in females that received 5,000 ppm but not in the lower dose groups. Necrosis of the renal tubular epithelium was observed in 2/9 males that received 5,000 ppm. Based on these results, 2-year studies of nitrofurantoin were conducted by feeding diets containing 0, 1,300, or 2,500 ppm nitrofurantoin to groups of 50 male F344/N rats and to groups of 50 male and Nitrofurantoin, NTP TR 341 PEER REVIEW PANEL The members of the Peer Review Panel who evaluated the draft Technical Report on nitrofurantoin on July 14, 1987, and on April 18, 1988, are listed below. Panel members serve as independent scientists, not as representatives of any institution, company, or governmental agency. In this capacity, Panel members have five major responsibilities: (a) to ascertain that all relevant literature data have been adequately cited and interpreted, (b) to determine if the design and conditions of the NTP studies were appropriate, (c) to ensure that the Technical Report presents the experimental results and conclusions fully and clearly, (d) to judge the...

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“…These obstacles have caused preclinical laboratory efforts to gravitate toward less expensive and easier to implement optical methods for hypoxia imaging . Many optical, as well as PET and immunohistochemical, approaches rely on the selective reduction of nitroaromatic compounds under hypoxic conditions. − The first step in this reduction process forms the nitroaromatic radical anion (RNO 2 –• ) and can be mediated by a range of enzymes including cytochrome P450 reductase, cytochrome c reductase, xanthine oxidase, and lipoamide dehydrogenase . Molecular oxygen, however, can reverse this step by reoxidizing the radical anion with concomitant formation of superoxide.…”

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confidence: 99%

Kinetics-Based Measurement of Hypoxia in Living Cells and Animals Using an Acetoxymethyl Ester Chemiluminescent Probe

et al. 2019

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Oxygenation and tissue hypoxia play critical roles in mammalian biology and contribute to aggressive phenotypes in cancerous tumors, driving research to develop accurate and easy-toimplement methods for monitoring hypoxia in living cells and animal models. This study reports the chemiluminescent probe HyCL-4-AM, which contains a nitroaromatic sensing moiety and, importantly, an acetoxymethyl (AM) ester that dramatically improves operation in cells and animals. HyCL-4-AM provides a selective 60 000-fold increase in luminescence emission in the presence of rat liver microsomes (RLM). For cellular operation, the chemiluminescence response kinetics is sharply dependent on oxygen levels, enabling highly significant and reproducible measurement of hypoxia in living cells. Whole animal imaging experiments in muscle tissue and tumor xenografts show that HyCL-4-AM can differentiate between well oxygenated muscle tissue and hypoxic tumors, demonstrating potential for monitoring tumor reoxygenation via hyperoxic treatment.

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Mechanism of reduction of nitrofurantoin on liver microsomes

Cited by 13 publications

References 9 publications

The Metabolism of Separase Inhibitor Sepin-1 in Human, Mouse, and Rat Liver Microsomes

The Metabolism of Separase Inhibitor Sepin-1 in Human, Mouse, and Rat Liver Microsomes

NTP technical report on the toxicology and carcinogenesis studies of nitrofurantoin (CAS no. 67-20-9) in F344/N rats and B6C3F mice (feed studies) / National Toxicology Program.

Kinetics-Based Measurement of Hypoxia in Living Cells and Animals Using an Acetoxymethyl Ester Chemiluminescent Probe

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