![]() ![]() 13 Commensal gut and pathogenic bacteria can reduce chloramphenicol to the amine metabolite in vitro 15–17,74,75 and in animal models of anaerobic infections, the anaerobic gut bacterium Bacteroides fragilis was shown to metabolize chloramphenicol via nitroreduction. ![]() 2) has been suggested based on the association of the toxicity with the oral (but not intravenous) route of chloramphenicol administration. 73 The mechanism of hematological toxicity is unclear, but a potential involvement of an amine metabolite of chloramphenicol ( Fig. 72 Although effective in treatment of certain bacterial infections, the clinical utility of chloramphenicol is limited due to side effects such as neurotoxicity and hematological toxicity. ![]() 2) that was isolated from the culture of the soil Gram-positive bacterium Streptomyces venezuelae as an antibacterial agent active against Gram-positive and Gram-negative bacteria. The TRV for mammals is derived from the testicular and reproductive toxicity data of rats, which are sensitive at a no observed adverse effect level (NOAEL) of 0.75 milligrams per kilogram per day (mg/kg/day) for significant reproductive performance that were used to develop a NOAEL of 0.04 mg/kg/day and a lowest observed adverse effect level (LOAEL) of 0.2 mg/kg/day.Ĭhloramphenicol is a natural nitroaromatic compound ( Fig. The toxicity data on wildlife is limited to only mammalian species. The toxicity data of DNB was evaluated for the derivation of wildlife toxicity reference values (TRV) for m-DNB that are protective to wildlife. Environmental contamination by m-DNB may be hazardous to animals and is acutely toxic since it produces hematological, testicular, and neurological effects in animals. It is found in the environment as a byproduct of trinitrotoluene (TNT). The synthetic nitro-aromatic compound m-nitrobenzene (m-DNB) is used in explosives, dyes, and as an intermediate in the synthesis of chemicals. Gunda Reddy, in Wildlife Toxicity Assessments for Chemicals of Military Concern, 2015 Abstract This is also true for analogues based on heteroaromatic mustards such as 11.10. Overall, this strategy is not very useful, because the presence of two or more electron-deficient groups onto the benzene ring of a nitrophenyl mustard to ensure a high enough reduction potential results in a low cytotoxicity even after reductive activation of part of these groups. Accordingly, its 2,4-dinitro analogue (SN-23862), in which the electron-attracting properties of the second nitro group induce a higher-reduction potential, has a higher-hypoxic selectivity. The simplest such prodrug is the nitrophenyl mustard ( 11.9), but it shows only a modest hypoxic selectivity because, due to its low-reduction potential of about −515 mV, only a small amount of the drug is likely to be reduced. Since the alkylating reactivity of aromatic mustards is greatly determined by the electron density in the mustard nitrogen, enzymatic reduction of a nitro group on the aromatic ring to a hydroxylamine derivative can result in a higher potency of these compounds as DNA alkylating agents (see Section 2.4 of Chapter 5). ![]() Unfortunately, the hypoxia selectivity has not been observed in solid tumors, probably because the high-reduction potential (–303 mV) and the tight DNA binding of this compound slows its diffusion into hypoxic areas. Nitracrine is another nitro derivative with selective cytotoxicity in hypoxic cell cultures, and it has been shown that besides its DNA intercalating properties it is able to alkylate DNA following reduction by thiols or enzymes, though the nature of the electrophilic metabolites generated in the bioreductive process is still debated. Enhanced cytotoxicity of RSU-1069 in hypoxic environments. ![]()
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