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PubMed1986

Mechanism of ubiquitin carboxyl-terminal hydrolase. Borohydride and hydroxylamine inactivate in the presence of ubiquitin.

Ubiquitin (Ub) carboxyl-terminal hydrolase (E) catalyzes the hydrolysis, at the Ub-carboxyl terminus, of a wide variety of C-terminal Ub derivatives. We show that the enzyme is inactivated by millimolar concentrations of either sodium borohydride or hydroxylamine, but only if Ub is present. We have interpreted these results on the assumption that the hydrolase mechanism is one of nucleophilic catalysis with an acyl-Ub-E intermediate. The borohydride-inactivated enzyme has the following properties. It is a stoichiometric complex of E and Ub containing tritium from sodium boro[3H]hydride. This complex is stable at neutral pH in 5 M urea and can be isolated on the basis of size on a sieving column, but a labeled product the size of Ub is released under more strongly denaturing conditions. The "Ub" released in acid is Ub-carboxyl-terminal aldehyde, based on the observations that: it contains the tritium present in the reduced complex and it is able to form the inactive enzyme from a stoichiometric amount of fresh enzyme, and inactivation is accompanied by E-Ub adduct formation; it has chemical properties expected of an aldehyde: after a second reduction of the Ub released with boro[3H]hydride and complete acid hydrolysis, tritium counts are found in ethanolamine (the carboxyl-terminal residue of Ub is glycine). These results suggest that enzyme and Ub combine in an equilibrium reaction to form an ester or thiol ester adduct (at the Ub-carboxyl terminus), and that this adduct is trapped by borohydride to give a very stable inactive E-Ub (thio) hemiacetal which is unable to undergo a second reduction step and which can release Ub-aldehyde in mild acid. Inactivation in the presence of hydroxylamine of hydrolase occurs once during hydrolysis of 1200 molecules of Ub-hydroxamate by the enzyme. The hydrolysis/inactivation ratio is constant over the range of 10-50 mM hydroxylamine showing that forms of E-Ub with which hydroxylamine and water react are different and not in rapid equilibrium. The inactive enzyme may be an acylhydroxamate formed from an E-Ub mixed anhydride generated from the E-Ub (thiol) ester inferred from the borohydride study. A direct radioactive assay for the hydrolase has been developed using the Ub-C-terminal amide of [3H]butanol-4-amine as substrate.

Animals↗
PubMed1985

Amino acid-specific ADP-ribosylation. Sensitivity to hydroxylamine of [cysteine(ADP-ribose)]protein and [arginine(ADP-ribose)]protein linkages.

Hydroxylamine stability has been used to classify (ADP-ribose)protein bonds into sensitive and resistant linkages, with the former representing (ADP-ribose)glutamate, and the latter, (ADP-ribose)arginine. Recently, it was shown that cysteine also serves as an ADP-ribose acceptor. The hydroxylamine stability of [cysteine([32P]ADP-ribose)]protein and [arginine([32P] ADP-ribose)]protein bonds was compared. In transducin, pertussis toxin catalyzes the ADP-ribosylation of a cysteine residue, whereas choleragen (cholera toxin) modifies an arginine moiety. The (ADP-ribose)cysteine bond formed by pertussis toxin was more stable to hydroxylamine than was the (ADP-ribose)arginine bond formed by choleragen. The (ADP-ribose)cysteine bond apparently represents a third class of ADP-ribose bonds. Pertussis toxin ADP-ribosylates the inhibitory guanyl nucleotide-binding regulatory protein (Gi) of adenylate cyclase, whereas choleragen modifies the stimulatory guanyl nucleotide-binding regulatory protein (Gs). These (ADP-ribose)protein linkages are identical in stability to those formed in transducin by the two toxins, consistent with the probability that cysteine and arginine are modified in Gi and Gs, respectively. Bonds exhibiting differences in hydroxylamine-stability were found in membranes from various non-intoxicated mammalian cells following incubation with [32P]NAD, which may reflect the presence of endogenous NAD:protein-ADP-ribosyl-transferases.

Adenosine Diphosphate Ribose↗
PubMed1983

Lack of correlation between cyclic GMP elevation and relaxation of nonvascular smooth muscle by nitroglycerin, nitroprusside, hydroxylamine and sodium azide.

Recent reports have suggested that the smooth muscle relaxant effects of drugs such as nitroprusside and nitroglycerin are mediated by increases in tissue levels of cyclic GMP. This hypothesis was examined by comparing the effects of nitroprusside, nitroglycerin, hydroxylamine and sodium azide on tension and cyclic GMP levels in rat vas deferens, rat myometrium and guinea-pig taenia coli. All four of the agents were capable of increasing cyclic GMP levels in these tissues but there did not appear to be a good correlation between cyclic GMP elevation and muscle relaxation in any of the tissues studied. For example, nitroprusside markedly elevated cyclic GMP levels in rat vas deferens and myometrium but had no relaxant effect on either tissue. Nitroglycerin was less effective than nitroprusside in elevating cyclic GMP levels, but was an effective relaxant in both tissues. Significant increases in myometrial cyclic GMP were seen with 0.1, 1 and 5 mM concentrations of hydroxylamine but only the highest concentration had a definite relaxant effect on the muscles. A similar concentration of nitroprusside produced a greater elevation of cyclic GMP than did hydroxylamine, but had no relaxant effect in this preparation. In guinea-pig taenia coli, significant increases in cyclic GMP levels were obtained with concentrations of sodium azide and hydroxylamine which had no effect on the contractile activity of the preparations. These results, together with previous results from this laboratory, suggest that the relaxant effects of this group of drugs in rat vas deferens, rat myometrium and guinea-pig taenia coli are not mediated by increases in tissue levels of cyclic GMP. Further experiments are necessary to determine whether a causal relationship exists between cyclic GMP elevation and relaxation in other types of smooth muscle.

Animals↗
PubMed1989

Vascular relaxation mediated by hydroxylamines and oximes: their conversion to nitrites and mechanism of endothelium dependent vascular relaxation.

Hydroxylamines (R-NHOH) and oximes (R = NOH) relax rat aortic rings independent of the presence of the endothelium. The relaxation is inhibited by methylene blue, an inhibitor of soluble guanylate cyclase and by hemoglobin, an inhibitor of the endothelium dependent relaxing factor (EDRF). Both the oximes and hydroxylamines generate NO/NO2- ions on treatment with iodine in glacial acetic acid. However, there is no correlation between relaxation and NO/NO2- formation. Compared to hydroxylamines, the oximes are less potent relaxing agents and not efficiently converted to NO/NO2- ions. We suggest that endothelium dependent relaxation is associated with a hydroxylamine like compound and is not directly related to NO.

Animals↗
PubMed1983

Differential survival and chloramphenicol-insensitive error-prone repair of hydroxylamine-inactivated phi X174 bacteriophage mutants.

Features of inactivation, repair and concomitant mutagenesis of hydroxylamine-treated phi X174 bacteriophages are reported here. (1) For reasons unknown, the nonsense phage mutants tested here were far more sensitive to hydroxylamine than the wild-type phage. In contrast, the sensitivities of these same phi X174 mutants to UV-irradiation are indistinguishable. (2) Hydroxylamine-treated amber phages mutated to ochre but not to wild-type particles, i.e., G leads to A transition events were recovered. (3) The repair of phi X174 phages from hydroxylamine-induced damage was error-prone, but unlike UV damage, did not require protein synthesis de novo. Possible mechanisms of these novel features are discussed.

Bacteriophage phi X 174↗
PubMed1987

Hydroxylamine effects on cryptogenic neoplasm development in C3H mice.

The effect of administration of hydroxylamine (HA) to male and female mice was studied because of reports suggesting an anticarcinogenic effect and an enhancement of lifespan. In this study, two C3H sublines were used: the C3H/HeN which carries a germinal provirus of the mouse mammary tumor virus and the C3H/HeJ(+) which also carries the milk-transmitted exogenous virus. Lifetime administration of 10 mM HA in the drinking water resulted in a decrease in mammary neoplasm incidence in female C3H/HeN mice, but not in female C3H/HeJ(+) mice. Ovarian neoplasms and cysts were common in all groups, indicating ovarian dysfunction, but these were not affected by treatment. The incidences of other cryptogenic neoplasms found in controls in significant numbers, i.e. liver carcinomas, lymphomas, lung adenomas and adrenal cortex tumors were only marginally affected by the treatment. However, an increased incidence of vascular neoplasms of the spleen in hydroxylamine-treated female C3H/HeN mice and vascular neoplasms of the lymph nodes in hydroxylamine-treated male C3H/HeJ(+) mice indicated a subline-related action on the reticuloendothelial system. The survival of control mice was 35-58% at 2 years and this was not increased in either subline by hydroxylamine, which is interpreted to indicate that this antiioxidant does not increase lifespan of animals under conditions of maintenance that are adequate for good survival.

Animals↗
PubMed1991

Cellular metabolism of proxyl nitroxides and hydroxylamines.

Previous data from model systems indicated that the proxyl nitroxides should be especially resistant to bioreduction and therefore could be an effective solution to this often problematic characteristic of nitroxides. Therefore, we investigated the rate of reduction by cells and by the usual model system, ascorbate, of four proxyl nitroxides and three reference nitroxides. We found that, while the rate of reduction by ascorbate of the proxyl nitroxides was slower than the rate of a prototypic pyrrolidine nitroxide (PCA), the reverse was true for reduction by cells. We also studied the rate of oxidation of the corresponding hydroxylamines. The rate of oxidation by cells of the proxyl hydroxylamines was relatively fast, especially for the most lipophilic derivative. These results indicate that: (i) proxyl nitroxides may not be unusually resistant to bioreduction by functional biological systems; (ii) accurate knowledge of relative rates of metabolism of nitroxides and hydroxylamines in cells and tissues will require direct studies in these systems because the rates may not closely parallel those observed in model (chemical) systems; and (iii) proxyl nitroxides show potential value as agents to measure oxygen concentrations by the rates of oxidation of their corresponding hydroxylamines.

Animals↗
PubMed2005

Kinetics and mechanism of the comproportionation reaction between oxoammonium cation and hydroxylamine derived from cyclic nitroxides.

Cyclic nitroxides demonstrate antioxidative activity in numerous in vitro and in vivo models, which frequently involves the participation of the reduced and oxidized forms of the nitroxide, namely, the hydroxylamine and oxoammonium cation. Generally, cellular reducing equivalents facilitate rapid enzymatic as well as nonenzymatic reduction of nitroxides in the tissue. On the other hand, the reaction of nitroxides with various radicals yields the highly oxidizing oxoammonium cation, which mediates the catalytic effect of nitroxides in selective oxidation of alcohols. Hence, nitroxides might act as both anti- and pro-oxidants. Therefore, the comproportionation reaction between the oxoammonium cation and the hydroxylamine might play a role in lowering the pro-oxidative activity of nitroxides. Although the comproportionation reaction has previously been studied, there is no agreement regarding its kinetic features. We investigated the reaction of the reduced forms of 2,2,6,6-tetramethylpiperidinoxyl (TPO) and 4-OH-2,2,6,6-tetramethylpiperidinoxyl (4-OH-TPO) with the oxoammonium cation derived from TPO at various pHs using rapid-mixing stopped-flow and EPR spectrometry. From the pH dependence of the reaction rate constants we determined the pK(1) of the respective hydroxylamines to be 7.5 and 6.9, respectively. The reduction potentials of the hydroxylamines were determined by cyclic voltammetry, and from their dependence on pH, we obtained the same pK(1) values. The rate constant of the comproportionation reaction does not exceed 20 M(-1) s(-1) in the physiological pH range and, therefore, cannot greatly contribute toward recycling of the nitroxides in the tissue.

Cations↗
PubMed1998

Reactivity of 6-phosphogluconolactone with hydroxylamine: the possible involvement of glucose-6-phosphate dehydrogenase in endogenous glycation reactions.

The reactivity of 6-phosphogluconolactone and of delta-gluconolactone with hydroxylamine (a model compound in electrophilicity determination studies) was examined and compared with the reactivity of several other electrophiles, such as acid anhydrides and esters, some of which exhibit adverse biological effects (e.g. carcinogenicity). At pH 7.6 and 30 degrees C, and with an excess of hydroxylamine concentration, most of the compounds tested disappear from the medium in a monoexponential reaction. On the other hand, the reaction of 6-phosphogluconolactone with hydroxylamine is biexponential. This finding indicates the existence of 6-phosphogluconolactone in two interconvertible, isomeric forms. The reactivity, towards hydroxylamine, of 6-phosphogluconolactone and, to a lesser extent of delta-gluconolactone, is on the upper scale of reactivity of the electrophiles tested. It is concluded that 6-phosphogluconolactone (and in particular, one of its isomeric forms) is a highly electrophilic compound, and may possibly react with sundry intracellular nucleophiles, thereby exerting untoward metabolic effects. In this connection, it is of interest that a positive correlation has been found to exist between glucose-6-phosphate dehydrogenase activity and cell proliferation.

Ammonium Hydroxide↗
PubMed2002

Ion chromatographic determination of trace hydroxylamine in waste streams generated by a pharmaceutical reaction process.

Hydroxylamine is a key raw material used in a synthetic drug process at Pharmacia. Since hydroxylamine is harmful to microorganisms, concentrations above 5 ppm could interfere with the biological sewage plant performance. This necessitated the development of a sensitive analytical method for detecting low levels of hydroxylamine in the waste streams generated from the pharmaceutical process. The present report describes a cation-exchange chromatographic method coupled with pulsed amperometric detection at a gold electrode for trace analysis of hydroxylamine. This method was evaluated by generating data on the parameters of specificity, precision, linearity, recovery and sensitivity.

Cation Exchange Resins↗
PubMed1977

Hydroxylamine oxidoreductase from Nitrosomonas: inactivation by hydrogen peroxide.

Incubation of hydroxylamine oxidoreductase of Nitrosomonas with hydrogen peroxide resulted in the rapid and irreversible loss of the ability to catalyze the dehydrogenation of hydroxylamine in the presence of electron acceptors, such as phenazine methosulfate. The rate of the reaction was dependent on the concentration of enzyme and H2O2. Inactivation occurred most rapidly at pH values between 9 and 10. Inactivation of the enzyme by H2O2 did not result in alteration of absorption spectrum of either the oxidized form of the enzyme or dithionite-reduced enzyme cytochromes with alpha maxima in the wavelength range 540-570 nm, indicating that those cytochromes were not directly involved in the dehydrogenase step. In contrast to the active enzyme, cytochromes with alpha maxima in the wavelength range 540-570 nm were not reducible by hydroxylamine in the inactivated enzyme. The dithionite-induced absorption maximum at 460 nm (cytochrome P 460), present in the active enzyme, was lost upon inactivation of the enzyme. This is the first direct indication of the involvement of cytochrome P 460 in the action of hydroxylamine oxidoreductase. Protection from inactivation was afforded by (a) substrates for the reduction of enzyme cytochrome, hydrazine, and N-methylhydroxylamine; (b) metal binding agents, KCN, 1,2-dihydroxybenzene-3,5-disulfonate, and hydroxyurea; (c) reductants, o-dianisidine, p-phenylenediamine, hydroquinone, pyrogallol, and dithiothreitol; (d) electron acceptors, phenazine methosulfate, and 2,6-dichlorophenolindophenol; and (e) the singlet oxygen trapping agent, 1,3-diphenylfuran. Scavengers of superoxide anion or hydroxyl radical did not protect the enzyme from inactivation.

Hydrogen Peroxide↗
PubMed1998

Effect of long-term ammonia starvation on the oxidation of ammonia and hydroxylamine by Nitrosomonas europaea.

Axenic cultures of the ammonia-oxidizing bacterium Nitrosomonas europaea were starved of ammonia (energy source) for up to 342 d. During this time the bacteria retained the ability to respond instantly to ammonia (1 mM) or hydroxylamine (0.1 mM) amendment by oxidizing it to nitrite without initial protein synthesis. In vivo, the ability to oxidize amended ammonia stayed almost constant during the starvation period, but a drop in the hydroxylamine oxidation rate (to 33%) was observed after 4 wk of starvation when exogenous hydroxylamine was supplied as sole energy source. In contrast, it has been shown that the level and in vitro activity of hydroxylamine oxidoreductase were not significantly affected during the starvation period. Only minor changes were detected between the protein patterns on one-dimensional SDS-PAGE of growing and starved cells. Thus, it is concluded that the activities of the energy-generating enzymes in N. europaea were not affected during long-term ammonia starvation.

Ammonia↗
PubMed2006

Reversion of structure-activity relationships of antitumor platinum complexes by acetoxime but not hydroxylamine ligands.

The presence of cis-configured exchangeable ligands has long been considered a prerequisite for antitumor activity of platinum complexes, but over the past few years, several examples violating this structure-activity relationship have been recognized. We report here on studies with the geometric isomers of [PtCl2(acetoxime)2], cis-[dichlorobis(acetoxime)platinum(II)] [1 (cis)] and trans-[dichlorobis(acetoxime)platinum(II)] [2 (trans)], as well as those of [PtCl2(hydroxylamine)2], cis-[dichlorobis(hydroxylamine)platinum(II)] [3 (cis)] and trans-[dichlorobis(hydroxylamine)platinum(II)] [4 (trans)]. We found that 2 (trans)is 16 times more cytotoxic than 1 (cis) and as cytotoxic as cisplatin in cisplatin-sensitive ovarian carcinoma cells (CH1). Moreover, 2 (trans) is 15 times more cytotoxic than either cisplatin or 1 (cis) in intrinsically cisplatin-resistant colon carcinoma cells (SW480). Thus, compound 2 (trans) represents a novel type of active platinum(II) complexes of the trans geometry, whereas the hydroxylamine-containing complexes conform to the classic structure-activity relationships. The reactivity of the compounds toward dGMP and DNA and their capacity to alter the structure of double-stranded DNA and form interstrand cross-links were studied by capillary electrophoresis and gel electrophoresis. The slow binding of 2 (trans) to dGMP (tau(1/2) = 50 h versus 8.9 h in the case of cisplatin), the low reactivity toward DNA, the comparatively small impact on DNA secondary structure, and the lack of detectable interstrand cross-linking suggest a mode of action fundamentally different from that of cisplatin. Implications of our findings for the minimal structural requirements (e.g., planarity around the nitrogen donor atom and/or ramified aliphatic moiety attached to the latter) of active trans-configured platinum complexes are discussed.

Antineoplastic Agents↗
PubMed1971

Prophage induction in lysogenic Escherichia coli with simple hydroxylamine and hydrazine compounds.

The prophage-inducing capability of hydroxylamine sulfate and 36 of its derivatives, and of hydrazine dihydrochloride and dihydrazine sulfate and 43 of their derivatives, was determined in Escherichia coli W1709 (lambda). Maximal nontoxic concentrations up to 1 mg/ml were tested. Hydroxylamine sulfate was active at 2.5 mug/ml and the following 17 derivatives were active at concentrations ranging up to 500 mug/ml: alpha-naphthylhydroxylamine, N-hydroxy-2-aminofluorene, oxamyl hydroxamic acid, O-carbamoyl hydroxylamine (isohydroxyurea), N-hydroxyurethane, N-methylhydroxylamine HCl, salicylhydroxamic acid, oxalohydroxamic acid, methoxyamine HCl, ethoxyamine HCl, N, N-diethylhydroxylamine oxalate, formaldoxime, formamidoxime, acetohydroxamic acid, acetaldoxime, acetone oxime, and hydroxyguanidine sulfate. Hydrazine dihydrochloride and dihydrazine sulfate were effective inducers at 5.0 and 2.5 mug/ml, respectively, and the following nine derivatives of them were active at concentrations ranging up to 500 mug/ml: phthalic acid hydrazide, phenylhydrazine HCl, p-nitrophenylhydrazine, p-chlorophenylhydrazine HCl, formylhydrazine, carbohydrazide, semicarbazide HCl, 1-methyl-1-phenyl-hydrazine sulfate, and acetic acid hydrazide. Nineteen hydroxylamine and 34 hydrazine derivatives were ineffective as inducers. Application of the prophage-induction system as a tool for detection of responsive hydroxylamino and hydrazino compounds which may be potential toxicological hazards in the environment is discussed.

Coliphages↗
PubMed1968

Nitrite formation from hydroxylamine and oximes by Pseudomonas aeruginosa.

Nitrite was formed from hydroxylamine and several oximes by intact cells and extracts of Pseudomonas aeruginosa. The activity was induced by the presence of oximes in the culture medium. Nitroalkanes were not intermediates in the conversion of acetaldoxime, acetone oxime, or butanone oxime to nitrite, since nitromethane inhibited the formation of nitrite from the nitro compounds but not from the corresponding oximes. The oxime apparently functions as a constant source of hydroxylamine during growth of the bacterium. Hydroxylamine at low concentration was converted stoichiometrically to nitrite by extracts of the bacterium; high concentrations were inhibitory. Nicotinamide adenine dinucleotide phosphate, oxygen, and other unidentified cofactors were necessary for the reaction. Actively nitrifying extracts possessed no hydroxylamine-cytochrome c reductase activity. Hyponitrite, nitrous oxide, and nitric oxide were not metabolized.

Hydrogen-Ion Concentration↗
PubMed1990

Sterically-hindered hydroxylamines as bioactive spin labels.

The use of sterically hindered hydroxylamines for the regulation of free radical reactions in biological systems and for the pharmacological correction of pathological conditions is described. They are shown to possess a number of advantages over nitroxyl radicals. They are more soluble in water, are less toxic and are easily oxidized to nitroxyl radicals in aqueous solutions. Hindered hydroxylamines can be also used for the study of pharmacokinetics of bioactive spin labels by the EPR technique. Pharmacokinetic parameters for spin-labeled analogues of tetronal are evaluated. Sulfur-containing hindered hydroxylamines are effective bioantioxidants, inhibiting efficiently the LPO of the microsomal fraction of liver and ADP- and thrombin induced plasma platelet aggregation. They increase also the survival of animals under ischemic shock. A cyclic mechanism for its antioxidative action is suggested. Recent data on the influence of the nitroxyl in equilibrium hydroxylamine moiety on bio-activity are summarized.

Animals↗
PubMed1977

Stimulation of guanylate cyclase by sodium nitroprusside, nitroglycerin and nitric oxide in various tissue preparations and comparison to the effects of sodium azide and hydroxylamine.

Sodium nitroprusside, nitroglycerin, sodium azide and hydroxylamine increased guanylate cyclase activity in particulate and/or soluble preparations from various tissues. While sodium nitroprusside increased guanylate cyclase activity in most of the preparations examined, the effects of sodium azide, hydroxylamine and nitroglycerin were tissue specific. Nitroglycerin and hydroxylamine were also less potent. Neither the protein activator factor nor catalase which is required for sodium azide effects altered the stimulatory effect of sodium nitroprusside. In the presence of sodium azide, sodium nitroprusside or hydroxylamine, magnesium ion was as effective as manganese ion as a sole cation cofactor for guanylate cyclase. With soluble guanylate cyclase from rat liver and bovine tracheal smooth muscle the concentrations of sodium nitroprusside that gave half-maximal stimulation with Mn2+ were 0.1 mM and 0.01 mM, respectively. Effective concentrations were slightly less with Mg2+ as a sole cation cofactor. The ability of these agents to increase cyclic GMP levels in intact tissues is probably due to their effects on guanylate cyclase activity. While the precise mechanism of guanylate cyclase activation by these agents is not known, activation may be due to the formation of nitric oxide or another reactive material since nitric oxide also increased guanylate cyclase activity.

Animals↗
PubMed1988

Role of dapsone hydroxylamine in dapsone-induced hemolytic anemia.

The hemolytic anemia which frequently accompanies treatment of individuals with dapsone and other arylamine drugs is believed to be caused not by the parent drugs per se, but rather by metabolites which are formed during the clearance of the drugs in vivo. To determine whether the N-hydroxyarylamine metabolites of dapsone could be responsible for dapsone-induced hemolysis, dapsone, dapsone hydroxylamine (DDS-NOH) and monoacetyldapsone hydroxylamine were administered to rats which had previously received 51Cr-labeled red blood cells. All three compounds caused an increase in the rate of disappearance of radioactivity from the blood as compared with saline-treated controls. In parallel in vitro studies, incubation of 51Cr-labeled red blood cells with DDS-NOH, but not dapsone or monoacetyldapsone, induced a decrease in survival time of the radiolabeled cells when they were reintroduced into isologous rats. The disappearance of radioactivity from the blood was matched by its selective uptake into the spleen. The amount of damage (as measured by decreased red cell survival in vivo) was proportional to both concentration and time of exposure to DDS-NOH. The area under the blood concentration vs. time curve for total arylhydroxylamines (DDS-NOH + monacetyldapsone hydroxylamine) in rats given a hemotoxic dose of dapsone was similar to that of rats given an equitoxic dose of DDS-NOH. Collectively, these data indicate that the hydroxylamine metabolites of dapsone are direct acting hemolytic agents that are formed from dapsone in sufficient amounts to account for their being the sole mediators of dapsone-induced hemolytic anemia in the rat.

Anemia, Hemolytic↗