Toxicity hydroxylamines

N-Hydroxylation of aniline and 4-chloroaniline by rainbow trout to hydroxylamines that could plausibly account for the subchronic toxicity of the original compounds (Dadyetal. 1991). 

Oxidation of cyclic and acyclic hydroxylamines with yellow mercuric oxide appears to proceed with high regioselectivity (109-115). Regioselectivity is determined by the electronic nature of the substituents (116). The oxidative regioselectivity of Mn02 is comparable to that of HgO, but due to its lower toxicity, it has been proposed to use Mn02 rather than HgO (Table 2.2) (117). 

The anammox catabolism, an exceptionally slow process generating toxic intermediates (hydroxylamine and hydrazin), takes place in an intracytoplasmic compartment called the anammoxosome. A surrounding impermeable membrane protects the cytoplasm from the toxic molecules produced inside this organelle-like structure. Such a tight barrier against diffusion seems to be realised by four-membered aliphatic cyclobutane rings that have been found... 

Derelanko, M.J., Gad, S.C., Gavigan, F.A., Babich, P.C. and Rinehart, W.E. (1987). Toxicity of hydroxylamine sulfate following dermal exposure Variability with exposure method and... 

Misonidazole [27 l-methoxy-3-(2-nitroimidazol-l-yl)-2-propanol] and the model compound l-methyl-2-nitroimidazole have been used as radiosensitizers in the treatment of certain types of human tumors. One important property of these compounds is that they are more toxic to hypoxic cells than to aerobic cells, indicating that reductive metabolism of the drug is involved in the toxicity. Results of a number of studies suggest that intracellular thiols play a significant role in the hypoxic cell toxicity, and it was found that reduction products formed stable thio ethers with GSH (for literature see References 181-183). The reaction mechanism of thio ether formation has not been fully established. It has been suggested that the 4-electron reduction product was involved in thio ether formation181,184,185, and that the hydroxylamine rather than the nitroso derivative was the reactant. On the other hand, an intermediate nitroso derivative is expected to give a sulfenamide cation (see Scheme 1) which easily allows thio ether formation. 

For insufficiently understood reasons, there exist relatively few reports on the use of phenols and hydroxylamines as pro-moieties of active carboxylic acids. Medicinal chemists perhaps perceive these pro-moieties as potential sources of toxicity problems (see below). Furthermore, an aryl pro-moiety may unfavorably influence on solubility. 

Esters ofN,N-dialkylhydroxylamines ((acyloxy)amines) appear to be possible candidates for prodrugs of carboxylic acids, but more studies must be published before any firm conclusion can be drawn. First, there are indications of low acute toxicity for N,N-(1 al ky I hydroxy Iambics [87], Whether the same applies (acutely and chronically) to the pro-moieties after their release from the prodrugs is not known. A second argument is the low basicity of hydroxylamines (the pKa of Ar,AT-dimethylhydroxylamine is 5.2), and the expected lower basicity of O-acylatcd hydroxylamines. As a result, esters of hydroxylamines will be in the unprotonated, more lipophilic form at physiological pH and should be absorbed more readily than the corresponding carboxylic acid [88]. 

Fig. 8.22 Structures of sulfamethoxazole and dapsone, drugs which form toxic hydroxylamine metabolites.

Embryotoxic effects have occurred in rabbits exposed to hydroxylamine hydrochloride by intracoelomic injection. Subcutaneous or intravenous injection of pregnant rabbits with 50-650mg of hydroxylamine hydrochloride on gestational day 12 caused death or euthanasia of all rabbits within 30 hours. All maternally injected rabbits exhibited severe cyanosis, presumably due to methemoglobinemia. At 8 hours all embryos were dead from cardiovascular effects, which are considered to be secondary to the severe maternal toxicity. 

Hydroxylamine is a direct-acting developmental toxicant only under conditions of direct embryonic exposure intracoelomic injection into the chorionic cavity of developing embryos of 100 pg of hydroxylamine caused deaths in 31 of 32 embryos. In general, exposure to hydroxylamine would kill the mother before levels within the embryo became sufficiently high to cause direct developmental toxicity. 

DeSesso JM, Goeringer GG Developmental toxicity of hydroxylamine an example of a maternally mediated effect. Toxicol Ind Health 6 109-121, 1990... 

Whenever Fe oxides, especially ferrihydrite, are formed in nature, a range of toxic or unwanted elements is coprecipitated. A case of natural detoxification of arsenic by Fe oxides was observed on the Coral Reef of Amberlite Island, Papua New Guinea. Upon reaching the aerobic surface waters, hydrothermal fluids rich in dissolved As and Fe, lose their As (and Fe) almost completely by adsorption on and/or coprecipitation of 2-line ferrihydrite. The precipitate contained (besides tens of mg of Cu, Pb, Zn) 55g/ kg As, and, thus, it prevented any damage to the biota (Pichler Veizer, 1999). Arsenic peaks (0.1-0.6 xM) at a depth of 2-6 cm in surficial sediments in 16 Canadian lakes were closely correlated with hydroxylamine reducible Fe (0.2-1 mM), suggesting again a close association between As and poorly ordered Fe oxides (Belzile Tes-sier, 1990). 

Hydroxylamine hydrochloride is moderately toxic by ingestion and subcutaneous and intraperitoneal administration. The oral LD50 in mice is in the... 

Cribb, A.E. et al. (1991) Reactions of the nitroso and hydroxylamine metabolites of sulfamethoxazole with reduced glutathione. Implications for idiosyncratic toxicity. Drug Metabolism and Disposition The Biological Fate of Chemicals, 19 (5), 900-906. 

Hydroxylamine acid sulfate. NH2OH.H2S04 mw 131.12, N 10.68%, white to brown crysts v hygrosc, mp indefinite, bp decomp sol w, MeOH si sol EtOH. Toxic and may explode on heating. 

This reaction yields HA in an anhydrous medium CH3 N02 +H2 S04 =HOS02 CCH NOH(I) (I)+2H20=H2S04+HC00H+NH20H or H2S04 + CO+NH2 OH (Ref 1), Hydroxylamine sulfate is highly toxic. Its uses are similar to those for the acid sulfate... 

Fortunately, there is now a comprehensive body of knowledge on the metabolic reactions that produce reactive (toxic) intermediates, so the drug designer can be aware of what might occur, and take steps to circumvent the possibility. Nelson (1982) has reviewed the classes and structures of drugs whose toxicities have been linked to metabolic activation. Problem classes include aromatic and some heteroaromatic nitro compounds (which may be reduced to a reactive toxin), and aromatic amines and their N-acylated derivatives (which may be oxidized, before or after hydrolysis, to a toxic hydroxylamine or iminoquinone). These are the most common classes, but others are hydrazines and acyl-hydrazines, haloalkanes, thiols and thioureas, quinones, many alkenes and alkynes, benzenoid aromatics, fused polycyclic aromatic compounds, and electron-rich heteroaromatics such as furans, thiophenes and pyrroles. 

For example, it has been suggested that the adverse reactions caused by a number of drugs such as isoniazid, procainamide, hydralazine could be due to metabolic activation by myeloperoxidase in neutrophils. Thus neutrophils will metabolize procainamide (Fig. 4.38) to a hydroxylamine metabolite. In the presence of chloride ion, myeloperoxidase will produce hypochlorous acid, a strong oxidizing agent, which may be responsible for metabolic activation and toxicity. One of the products is N-chloroprocainamide (see also sect. "Hydralazine," chap. 7). 

Tertiary amine oxides and hydroxy la mines are also reduced by cytochromes P-450. Hydroxylamines, as well as being reduced by cytochromes P-450, are also reduced by a flavoprotein, which is part of a system, which requires NADH and includes NADH cytochrome b5 reductase and cytochrome b5. Quinones, such as the anticancer drug adriamycin (doxorubicin) and menadione, can undergo one-electron reduction catalyzed by NADPH cytochrome P-450 reductase. The semiquinone product may be oxidized back to the quinone with the concomitant production of superoxide anion radical, giving rise to redox cycling and potential cytotoxicity. This underlies the cardiac toxicity of adriamycin (see chap. 6). 

---